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Tremelimumab, a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) human monoclonal antibody of the immunoglobulin G2 kappa isotype, has been studied in oncology clinical trials as both monotherapy and in combination with durvalumab. This study characterized the pharmacokinetics of tremelimumab as monotherapy and in combination with durvalumab and evaluated the impact of patient covariates on pharmacokinetics.A pooled-analysis population pharmacokinetics model was built using NONMEM methodology. Pharmacokinetic data from 5 studies spanning different tumor types and therapy regimens were pooled for model development (956 patients). A dataset pooled from 4 additional studies was used for external validation (554 patients). Demographic and relevant clinical covariates were explored during model development.Tremelimumab exhibited linear pharmacokinetics, well described by a two-compartment model, with time-varying clearance (0.276 L/day at baseline) associated primarily with therapy regimen and linked with changes in disease status. As monotherapy and combination therapy, tremelimumab clearance over one year increased by ~16% and decreased by ~17%, respectively. Pharmacokinetic behavior was consistent across patient demographics and cancer subtypes. Patients with higher bodyweight and lower albumin levels at baseline had significantly higher clearance; however, no dosage adjustments are warranted. A flat dose (75 mg) was projected to provide comparable exposure to weight-based dosing (1 mg/kg) in adults.Tremelimumab exhibited linear pharmacokinetics but consistently opposite trends of time-varying clearance as monotherapy and in combination with durvalumab. Baseline bodyweight and albumin were significant covariates, but conversion from weight-based dosing at 1 mg/kg to flat dosing at 75 mg had no clinically relevant impact.

Supplementary Figure S1. Flow diagram of patients included in the PK analysis, exposure-response analysis, and PD analysis datasets

Purpose:A novel single-dose regimen of 300 mg tremelimumab in combination with durvalumab [Single Tremelimumab Regular Interval Durvalumab (STRIDE)] has demonstrated a favorable benefit-risk profile in the phase I/II Study 22 (NCT02519348) and phase III HIMALAYA study (NCT03298451). This study evaluated the pharmacokinetics, exposure–response, and exposure–pharmacodynamics relationships of tremelimumab in patients with unresectable hepatocellular carcinoma (uHCC).Patients and Methods:A previous tremelimumab population pharmacokinetic model was validated using data from parts 2 and 3 of Study 22. Exposure–response analyses explored relationships of tremelimumab exposure with efficacy and safety. Pharmacokinetics and pharmacodynamics relationships were evaluated using linear and nonlinear regression models.Results:The observed pharmacokinetics of tremelimumab in uHCC were consistent with predictions; no significant covariates were identified. Tremelimumab exposure was not significantly associated with adverse events, objective response rate, or progression-free survival. Overall survival (OS) was longer for patients with tremelimumab exposure, minimum serum drug concentration (Cmin1) ≥ median versus Cmin1 < median (18.99 months vs. 10.97 months), but this exposure-survival analysis might be confounded with baseline characteristics of albumin level and neutrophil to lymphocyte ratio, which had a significant impact on OS (P = 0.0004 and 0.0001, respectively). The predicted Cmin1 of tremelimumab in STRIDE regimen (12.9 μg/mL) was greater than the estimated concentration of tremelimumab eliciting half-maximal increases (EC50 = 5.24 μg/mL) in CD8+Ki67+ T-cell counts.Conclusions:Our findings support novel insights into tremelimumab pharmacokinetics and exposure–response relationships in HCC and support the clinical utility of the STRIDE regimen in patients with uHCC.

Supplementary Figure S3. CFB of proliferating CD8+Ki67+ T cells vs predicted tremelimumab exposure (PD analysis population) in patients with lower and higher baseline CD8+Ki67+ T-cell counts

Supplementary Figure S2. The effect of covariates, body weight, baseline albumin level, and combination therapy, on tremelimumab exposure metric Cmin1 (PK analysis population)

Supplementary Data for publication

Clinical drug interaction studies with itraconazole and rifampicin have demonstrated that acalabrutinib is a sensitive substrate of CYP3A. A physiologically based pharmacokinetic (PBPK) model was developed based on the data of these studies. One of the active CYP3A metabolites, ACP-5862, was identified but never studied in a drug interaction scenario. This study aims to evaluate both parent and metabolite exposure change with coadministration of moderate CYP3A inhibitors and its impact on safety and efficacy.In an open label, randomized, 2-period study, we investigated the effect of coadministration of fluconazole or isavuconazole on the pharmacokinetics of acalabrutinib. Bruton tyrosine kinase receptor occupancy and safety were compared between different treatments. Experimental data were compared to PBPK simulation results.Least square means of acalabrutinib maximum plasma concentration and area under the curve increased 1.37 (1.14-1.64) and 1.60 (1.45-1.77)-fold in the presence of isavuconazole and 1.48 (1.10-1.98) and 2.16 (1.94-2.40)-fold in the presence of fluconazole, respectively. For ACP-5862, these values are 0.72 (0.63-0.82) and 0.91 (0.86-0.97) fold for isavuconazole and 0.65 (0.49-0.87) and 0.95 (0.91-0.99) fold for fluconazole coadministration. The PBPK model was able to recover acalabrutinib and ACP-5862 PK profiles in the study. Bruton tyrosine kinase receptor occupancy change was minimal in the presence of isavuconazole. There were no deaths, serious adverse events (AEs), or subject discontinuation due to AEs in this study. Only mild (Grade 1) AEs were reported during the study, by 17% of the study population.Our results demonstrate the impact of fluconazole and isavuconazole on the pharmacokinetics of acalabrutinib and ACP-5862, and suggest that no dose adjustment is needed for concomitant administration with moderate CYP3A inhibitors. the current PBPK model can be used to propose dose adjustment for drug interactions via CYP3A.

Purpose:A novel single-dose regimen of 300 mg tremelimumab in combination with durvalumab [Single Tremelimumab Regular Interval Durvalumab (STRIDE)] has demonstrated a favorable benefit-risk profile in the phase I/II Study 22 (NCT02519348) and phase III HIMALAYA study (NCT03298451). This study evaluated the pharmacokinetics, exposure–response, and exposure–pharmacodynamics relationships of tremelimumab in patients with unresectable hepatocellular carcinoma (uHCC).Patients and Methods:A previous tremelimumab population pharmacokinetic model was validated using data from parts 2 and 3 of Study 22. Exposure–response analyses explored relationships of tremelimumab exposure with efficacy and safety. Pharmacokinetics and pharmacodynamics relationships were evaluated using linear and nonlinear regression models.Results:The observed pharmacokinetics of tremelimumab in uHCC were consistent with predictions; no significant covariates were identified. Tremelimumab exposure was not significantly associated with adverse events, objective response rate, or progression-free survival. Overall survival (OS) was longer for patients with tremelimumab exposure, minimum serum drug concentration (Cmin1) ≥ median versus Cmin1 < median (18.99 months vs. 10.97 months), but this exposure-survival analysis might be confounded with baseline characteristics of albumin level and neutrophil to lymphocyte ratio, which had a significant impact on OS (P = 0.0004 and 0.0001, respectively). The predicted Cmin1 of tremelimumab in STRIDE regimen (12.9 μg/mL) was greater than the estimated concentration of tremelimumab eliciting half-maximal increases (EC50 = 5.24 μg/mL) in CD8+Ki67+ T-cell counts.Conclusions:Our findings support novel insights into tremelimumab pharmacokinetics and exposure–response relationships in HCC and support the clinical utility of the STRIDE regimen in patients with uHCC.

Selumetinib (ARRY-142886), an oral, potent and highly selective allosteric mitogen-activated protein kinase kinase 1/2 inhibitor, is approved by the US Food and Drug Administration for the treatment of pediatric patients aged ≥2 years with neurofibromatosis type 1 with symptomatic, inoperable plexiform neurofibromas. A physiologically based pharmacokinetic (PBPK) model was constructed to predict plasma concentration-time profiles of selumetinib, and to evaluate the impact of coadministering moderate cytochrome P450 (CYP) 3A4/2C19 inhibitors/inducers. The model was also used to extrapolate pharmacokinetic exposures from older children with different body surface area to guide dosing in younger children. This model was built based on physiochemical data and clinical in vivo drug-drug interaction (DDI) studies with itraconazole and fluconazole, and verified against data from an in vivo rifampicin DDI study and an absolute bioavailability study. The pediatric model was updated by changing system-specific input parameters using the Simcyp pediatric module. The model captured the observed selumetinib pharmacokinetic profiles and the interactions with CYP inhibitors/inducers. The predictions from the PBPK model showed a DDI effect of 30% to 40% increase or decrease in selumetinib exposure when coadministered with moderate CYP inhibitors or inducers, respectively, which was used to inform dose management and adjustments. The pediatric PBPK model was applied to simulate exposures in specific body surface area brackets that matched those achieved with a 25 mg/m2 dose in SPRINT clinical trials. The pediatric PBPK model was used to guide the dose for younger patients in a planned pediatric clinical study.

Purpose Limited information is available regarding the drug–drug interaction (DDI) potential of molecular targeted agents and rituximab plus cyclophosphamide, doxorubicin (hydroxydaunorubicin), vincristine (Oncovin), and prednisone (R-CHOP) therapy. The addition of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib to R-CHOP therapy results in increased toxicity versus R-CHOP alone, including higher incidence of peripheral neuropathy. Vincristine is a substrate of P-glycoprotein (P-gp, ABCB1); drugs that inhibit P-gp could potentially cause increased toxicity when co-administered with vincristine through DDI. While the combination of the BTK inhibitor acalabrutinib and R-CHOP is being explored clinically, the DDI potential between these therapies is unknown. Methods A human mechanistic physiology-based pharmacokinetic (PBPK) model of vincristine following intravenous dosing was developed to predict potential DDI interactions with combination therapy. In vitro absorption, distribution, metabolism, and excretion and in vivo clinical PK parameters informed PBPK model development, which was verified by comparing simulated vincristine concentrations with observed clinical data. Results While simulations suggested no DDI between vincristine and ibrutinib or acalabrutinib in plasma, simulated vincristine exposure in muscle tissue was increased in the presence of ibrutinib but not acalabrutinib. Extrapolation of the vincristine mechanistic PBPK model to other P-gp substrates further suggested DDI risk when ibrutinib (area under the concentration–time curve [AUC] ratio: 1.8), but not acalabrutinib (AUC ratio: 0.92), was given orally with venetoclax or digoxin. Conclusion Overall, these data suggest low DDI risk between acalabrutinib and P-gp substrates with negligible increase in the potential risk of vincristine-induced peripheral neuropathy when acalabrutinib is added to R-CHOP therapy.

Selumetinib (ARRY-142886) is a potent, selective, MEK1/2 inhibitor approved in the US for the treatment of children (≥ 2 years) with neurofibromatosis type 1 (NF1) and symptomatic, inoperable plexiform neurofibromas (PN). We characterized population pharmacokinetics (PK) of selumetinib and its active N‐desmethyl metabolite, evaluated exposure–safety/efficacy relationships, and assessed the proposed therapeutic dose of 25 mg/m2 bid based on body surface area (BSA) in this patient population. Population PK modeling and covariate analysis (demographics, formulation, liver enzymes, BSA, patients/healthy volunteers) were based on pooled PK data from adult healthy volunteers (n = 391), adult oncology patients (n = 83) and pediatric patients with NF1-PN (n = 68). Longitudinal selumetinib/metabolite exposures were predicted with the final model. Exposure–safety/efficacy analyses were applied to pediatric patients (dose levels: 20, 25, 30 mg/m2 bid). Selumetinib and metabolite concentration–time courses were modeled using a joint compartmental model. Typical selumetinib plasma clearance was 11.6 L/h (95% CI 11.0–12.2 L/ h). Only BSA had a clinically relevant (> 20%) impact on exposure, supporting BSA-based administration in children. Selumetinib and metabolite exposures in responders (≥ 20% PN volume decrease from baseline) and non-responders were largely overlapping, with medians numerically higher in responders. No clear relationships between exposure and safety events were established; exposure was not associated with key adverse events (AEs) including rash acneiform, diarrhea, vomiting, and nausea. Findings support continuous selumetinib 25 mg/m2 bid in pediatric patients. Importantly, the updated dosing nomogram ensures that patients will receive a clinically active, yet tolerable, dose regardless of differences in BSA and allows dose reductions, if necessary.

Acalabrutinib, a selective Bruton's tyrosine kinase inhibitor, is a biopharmaceutics classification system class II drug. The aim of this study was to develop a physiologically based pharmacokinetic (PBPK) model to mechanistically describe absorption of immediate release capsule formulation of acalabrutinib in humans. Integration of in vitro biorelevant measurements, dissolution studies and in silico modelling provided clinically relevant inputs for the mechanistic absorption PBPK model. The batch specific dissolution data were integrated in two ways, by fitting a diffusion layer model scalar to the drug product dissolution with integration of drug substance laser diffraction particle size data, or by fitting a product particle size distribution to the dissolution data. The latter method proved more robust and biopredictive. In both cases, the drug surface solubility was well predicted by the Simcyp simulator. The model using the product particle size distribution (P-PSD) for each clinical batch adequately captured the PK profiles of acalabrutinib and its active metabolite. Average fold errors were 0.89 for both Cmax and AUC, suggesting good agreement between predicted and observed PK values. The model also accurately predicted pH-dependent drug-drug interactions between omeprazole and acalabrutinib, which was similar across all clinical formulations. The model predicted acalabrutinib geometric mean AUC ratios (with omeprazole vs acalabrutinib alone) were 0.51 and 0.68 for 2 batches of formulations, which are close to observed values of 0.43 and 0.51~0.63, respectively. The mechanistic absorption PBPK model could be potentially used for future applications such as optimizing formulations or predicting the PK for different batches of the drug product.

Purpose The objective of this study was to improve the predictive performance of cytochrome P450 (CYP) 2C19 substrates in Japanese subjects using physiologically based pharmacokinetic (PBPK) modeling. Materials and methods Esomeprazole, a CYP2C19 substrate, was selected as a test compound, and the Simcyp simulator was used for pharmacokinetic prediction. The compound file of esomeprazole model developed in healthy Caucasian subjects was applied directly. The population file "Sim-Japanese" in Simcyp was adopted to predict esomeprazole pharmacokinetics in Japanese, while CYP2C19 enzyme abundances in the liver and the gastrointestinal tract for homozygous extensive metabolizers (homo EMs), heterozygous extensive metabolizers (hetero EMs), and poor metabolizers (PMs) were adjusted to be the same as in Caucasians. Results The PBPK model predicted esomeprazole exposure after 10-, 20-, and 40-mg doses in Japanese subjects within 1.5-fold of observed values in all three -CYP2C19 phenotypes. The reported concentration-time profiles were mostly well-captured within the 95% prediction intervals. Conclusion By adjusting CYP2C19 enzyme abundances levels in the Japanese population, the systemic exposure of esomeprazole in Japanese subjects can be reasonably extrapolated using a PBPK model developed in Caucasian subjects. This analysis serves as a case application for assessing the predictive performance of CYP2C19 substrate in Japanese subjects by using PBPK modeling approach.

Olaparib is a poly ADP-ribose polymerase inhibitor that induces synthetic lethality in tumors with deficient homologous recombination repair. Population exposure-response analyses were performed to evaluate the efficacy and safety of olaparib exposure in patients with cancer. Data from multiple phase I/II/III clinical studies from both capsule and tablet formulations were combined for efficacy (N = 410) and safety (N = 757) analyses. Exposure-progression-free survival (Cox proportional hazards model indicated that a 300 mg b.i.d. tablet was statistically superior to the 200 mg b.i.d. tablet dose (hazard ratio of 0.96), although the difference was small. Exposure-safety logistic regression models and hemoglobin models predicted similar probability of safety events or hemoglobin decrease with largely overlapping 95% confidence intervals at 300 mg b.i.d. tablet, 200 mg b.i.d. tablet, and 400 mg b.i.d. capsule. The analyses provided key assessments to support the approval of olaparib 300 mg tablet therapeutic dose in patients with ovarian and breast cancer, regardless of their breast cancer (BRCA) mutation status.

5050 Background: PROpel (NCT03732820) is a double-blind, Phase III trial of abiraterone + olaparib vs abiraterone + placebo as first-line treatment in patients with metastatic castration-resistant prostate cancer (mCRPC). Here we report results from the pharmacokinetics (PK) analysis of patients in PROpel. Methods: Patients were randomized 1:1 to receive abiraterone (1000 mg qd) plus prednisone/prednisolone with either olaparib (full monotherapy dose: 300 mg bid) or placebo. Eligible patients were biomarker unselected with confirmed prostate adenocarcinoma and castration-resistant metastatic disease. They had not received prior chemotherapy or next-generation hormonal agents (NHAs) for mCRPC. PK sampling was performed in a subset of patients. Concentrations of olaparib and abiraterone, and its active metabolite Δ4-abiraterone, were measured at steady state predose, at 30 min, 2 h, 3 h, 5 h, and 8 h postdose. The data underwent noncompartmental analysis to evaluate the effect of olaparib on abiraterone PK. The PK of olaparib in the presence of abiraterone was also compared with olaparib PK from other monotherapy studies to evaluate the effect of abiraterone on olaparib PK. Results: The PK analysis included 66 patients from the olaparib + abiraterone arm and 58 patients from the placebo + abiraterone arm. Olaparib absorption was rapid, with median tmax,ss of 2 h. Absorption of abiraterone was rapid in both treatment groups, with median tmax,ss observed between 2.00 and 2.04 h. The steady state exposure of olaparib in the presence of abiraterone, based on AUCss, Cmax,ss and Cmin,ss, was similar to observations for patients receiving olaparib 300 mg bid monotherapy in other Phase III studies, with values of 39.3 μg⋅h/mL, 6.3 μg/mL, and 1.0 μg/mL, respectively. Steady state exposures for abiraterone were similar between the two treatment arms (abiraterone + placebo: AUC(0–8) = 339.5 ng⋅h/mL, Cmax,ss = 105.4 ng/mL, Cmin,ss = 8.5 ng/mL; abiraterone + olaparib: AUC(0–8) = 393.7 ng⋅h/mL, Cmax,ss = 112.6 ng/mL, Cmin,ss = 7.7 ng/mL), and PK data for the abiraterone + olaparib arm were similar to those reported in the literature for abiraterone monotherapy. Conclusions: Combination treatment of olaparib ( full monotherapy dose: 300 mg bid) and abiraterone (1000 mg qd) in patients with mCRPC had no clinically significant effect on the PK profiles of either drug. The steady state exposures for abiraterone were similar between the two treatment arms, indicating that co-administration with olaparib 300 mg bid has no effect on the PK of abiraterone. In line with previous Phase II trial data, results from PROpel confirmed that there were no relevant PK based drug–drug-interactions between olaparib and abiraterone. Clinical trial information: NCT03732820.

In order to encourage innovative medicine to address Chinese unmet medical needs, China has changed its drug regulatory landscape to speed up access to new medicines. In order to understand the fast‐changing landscape and to enable planning of more global drug development programs and study designs in China, we reviewed 15 published clinical pharmacology‐related guidances by the National Medical Products Administration (NMPA), and compared them with reference guidances from the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), or the International Conference on Harmonization (ICH), to understand the similarities and differences, especially any China‐specific requirements, such as ethnic sensitivity analysis. Overall, by reviewing these clinical pharmacology‐related NMPA guidances, it is clear that NMPA guidances are very similar to FDA, EMA, and ICH guidances. There are no relevant differences in the major principles, but some differences in structure, contents, and focus were noted. The NMPA is adapting flexibility statements into newly published guidances. Ethnic sensitivity analysis needs to be implemented early in drug development plans. The NMPA encourages sponsors to conduct early clinical trials in China or include China early in multiregional clinical trials, and to obtain safety, efficacy, and pharmacokinetic data for ethnic sensitivity analysis. Depending on the stage of development, ethnic sensitivity analysis can be conducted using in vitro or literature data, other Asian clinical data, or Chinese clinical data.

Glycopyrronium bromide, a synthetic anticholinergic agent used to treat patients with chronic obstructive pulmonary disease (COPD), is eliminated from the body by renal excretion and therefore systemic exposure is expected to be increased in patients with decreasing renal function. Despite enrollment of patients with decreasing renal function to evaluate the impact of renal impairment on the pharmacokinetics of glycopyrronium in clinical studies, no patients with severe renal impairment were included. A physiologically based pharmacokinetic (PBPK) model was developed in patients with COPD with normal renal function and used to predict systemic exposure of glycopyrronium in patients with severe renal impairment. The model accurately predicted plasma concentration-time profiles in patients with normal renal function, and mild and moderate renal impairment; the predicted and observed AUC and Cmax in these populations were similar. Compared to patients with normal renal function, a 1.20-, 1.45-, and 1.59-fold increase AUC was predicted in patients with mild, moderate, and severe renal impairment, respectively, suggesting dose adjustment is not necessary in patients with renal impairment. In conclusion, PBPK models, verified with clinical study data from patients with normal renal function, can potentially be used to predict the pharmacokinetics and recommended dose adjustment for patients with renal impairment.

Ceftazidime‐avibactam is a novel β‐lactam/β‐lactamase inhibitor combination for the treatment of serious infections caused by resistant gram‐negative pathogens. Population pharmacokinetic (PopPK) models were built to incorporate pharmacokinetic (PK) data from five phase III trials in patients with complicated intra‐abdominal infection (cIAI), complicated urinary tract infection (cUTI), or nosocomial (including ventilator‐associated) pneumonia. Ceftazidime and avibactam pharmacokinetics were well‐described by two‐compartment disposition models, with creatinine clearance (CrCL) the key covariate determining clearance variability. Steady‐state ceftazidime and avibactam exposure for most patient subgroups differed by ≤ 20% vs. healthy volunteers. Probability of PK/pharmacodynamic (PD) target attainment (free plasma ceftazidime > 8 mg/L and avibactam > 1 mg/L for ≥ 50% of dosing interval) was ≥ 94.9% in simulations for all patient subgroups, including indication and renal function categories. No exposure‐microbiological response relationship was identified because target exposures were achieved in almost all patients. These modeling results support the approved ceftazidime‐avibactam dosage regimens (2000‐500 mg every 8 hours, adjusted for CrCL ≤ 50 mL/min).

Fulvestrant, the first-in-class selective estrogen receptor (ER) degrader (SERD), is clinically effective in patients with ERPatients were randomized 1:1 to receive AZD9496 250 mg twice daily from day 1 for 5-14 days, or fulvestrant 500 mg on day 1. On-treatment imaging-guided core tumor biopsies were taken between day 5 and 14 and compared with pretreatment diagnostic biopsies. The primary objective was to compare the effects of AZD9496 and fulvestrant on ER expression. Secondary objectives included changes in progesterone receptor (PR) and Ki-67 pharmacokinetic/pharmacodynamic relationships and safety.Forty-six women received treatment (AZD9496This was the first presurgical study to demonstrate that an oral SERD affects its key biological targets. However, AZD9496 was not superior to fulvestrant at the dose tested.

Selumetinib (AZD6244, ARRAY-142886) is a mitogen-activated protein kinase kinase inhibitor that has been tested for treatment of non-small cell lung cancer (NSCLC). Selumetinib (75 mg twice daily) plus docetaxel in patients with advanced NSCLC has been assessed in phase 2 (SELECT-2) and phase 3 (SELECT-1) clinical trials. The objective of the current analysis was to investigate the exposure-response relationship of selumetinib in these 2 clinical trials, based on the development of a population pharmacokinetic (PopPK) model for selumetinib and its active metabolite, N-desmethyl selumetinib, in patients with NSCLC. A PopPK model using data from seven phase 1 studies was first developed and served as prior information for the development of the patient PopPK model. The pharmacokinetics (PK) of selumetinib and N-desmethyl selumetinib were modeled simultaneously. A two-compartment model with zero-first order absorption and first-order elimination reasonably described the selumetinib PK. The N-desmethyl metabolite of selumetinib was described by a one-compartment model with first-order elimination. The final PK parameter estimates were similar between patients with NSCLC and patients in the phase 1 population. Selumetinib apparent clearance and central volume of distribution were 11.9 L/h and 32.1 L, respectively, in patients. Individual selumetinib exposure metrics were estimated to investigate the correlation between exposure and efficacy/safety endpoints observed in NSCLC studies. There was no significant difference in progression-free survival (the primary endpoint) among the different quartiles of exposure. Similarly, no significant correlation was observed between selumetinib exposure and other secondary efficacy or safety endpoints. The conclusions are in accordance with the reported clinical findings.

The accuracy of physiologically based pharmacokinetic (PBPK) model prediction in children, especially those younger than 2 years old, has not been systematically evaluated. The aim of this study was to characterize the pediatric predictive performance of the PBPK approach for 10 drugs extensively metabolized by CYP1A2 (theophylline), CYP2C8 (desloratidine, montelukast), CYP2C9 (diclofenac), CYP2C19 (esomeprazole, lansoprazole), CYP2D6 (tramadol), and CYP3A4 (itraconazole, ondansetron, sufentanil). Model performance in children was evaluated by comparing simulated plasma concentration-time profiles with observed clinical results for each drug and age group. PBPK models reasonably predicted the pharmacokinetics of desloratadine, diclofenac, itraconazole, lansoprazole, montelukast, ondansetron, sufentanil, theophylline, and tramadol across all age groups. Collectively, 58 out of 67 predictions were within 2-fold and 43 out of 67 predictions within 1.5-fold of observed values. Developed PBPK models can reasonably predict exposure in children age 1 month and older for an array of predominantly CYP metabolized drugs.

Background: The association between immune-mediated adverse events (imAEs) occurring after treatment with immunotherapy and patient outcomes is an important clinical question with prognostic relevance. When toxicity arises from anti-PD1/PD-L1, either alone or in combination with anti-CTLA-4 therapy, the immune system activation and auto-reactivity may also be reflective of an anti-tumor response. In this analysis, data from the MYSTIC clinical trial (NCT02453282) are used to evaluate whether there is an association between imAEs and efficacy in patients receiving anti-PD-L1 therapy alone or in combination with anti-CTLA-4. Methods: MYSTIC is a phase 3, randomized, open-label, multicenter, global study of first-line durvalumab as monotherapy or in combination with tremelimumab versus chemotherapy in patients with metastatic NSCLC. Individual patient-level data from 902 patients who participated in the trial were used in the analysis (307 in the monotherapy arm, 310 in the combination arm and 285 in the chemotherapy arm). imAE development was observed in 221 patients (84 in the monotherapy arm, 131 in the combination arm and 6 in the chemotherapy arm). Since imAEs were observed in only 6 out of 285 patients in the chemotherapy arm, the chemotherapy arm was not used in our analysis. Survival analysis (univariate and multivariate) was performed to assess the relationship between imAE development and patient outcomes. Results: Significant improvement in overall survival (OS) was observed in patients with any-grade imAEs compared to patients without imAEs, irrespective of their PD-L1 levels: HR 0.44 (95% CI 0.31-0.61) in the durvalumab monotherapy arm and HR 0.52 (95% CI 0.40-0.68) in the durvalumab + tremelimumab combination arm. After adjusting for confounders in multivariate analysis, significant OS benefit was seen in patients with imAEs in both IO arms: HR 0.49 (95% CI 0.35-0.69) in the monotherapy arm and HR 0.49 (95% CI 0.38-0.64) in the combination therapy arm. For patients with an early onset of imAE (within the first 3 months of treatment), significantly longer OS was observed in those who were able to continue with IO treatment after imAE occurrence compared to those who had to drop out: HR 0.36 (95% CI 0.09-0.39) in the monotherapy arm and HR 0.34 (95% CI 0.21-0.55) in the combination therapy arm. Similar trends were also observed for progression-free survival. High-grade (grade ≥3) imAEs were observed in very few patients in both IO arms, and no significant difference in patient outcome was observed when survival analysis was conducted taking severity of imAEs into account. Higher odds of imAE development was seen (odds ratio 3.02 [95% CI 1.56-5.83]) in RECIST responders compared to non-responders. Conclusion: In this retrospective analysis, a strong association was identified between imAE development and favorable efficacy outcome. Citation Format: Agnish Dey, Matthew Austin, Harriet Kluger, Nataliya Trunova, Helen Mann, Norah Shire, Diansong Zhou, Ganesh Mugundu. Association between immune-mediated adverse events and survival in patients with metastatic non-small cell lung cancer treated with durvalumab and tremelimumab [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 489.

Naloxegol is approved for the treatment of opioid-induced constipation (OIC) in adults with chronic noncancer pain. Population exposure-response models were developed using data from a phase II study comprising 185 adults with OIC. The weekly probability of response defined as having ≥3/week spontaneous bowel movements (SBMs) and ≥1 SBM/week increase over baseline was characterized by a longitudinal mixed-effects logistic regression dose-response model, and the probability of time to discontinuation was modeled with a Weibull distribution function. The predicted probability of SBM in a given week increased with increasing naloxegol dose. The model predicted that 12.5, 25, and 37.5 mg doses would produce median response rates of 40%, 50%, and 60%, and dropout rates of 13.3%, 16.7%, and 23.3%, respectively. The large overlap of predicted difference of the response rate between placebo and the 25 or 37.5 mg doses suggested little utility of using a 37.5 mg dose in phase III studies.

SummaryAims To characterise the pharmacokinetics (PK) of selumetinib (AZD6244; ARRY-142886), a MEK1/2 inhibitor in clinical development for numerous indications, and its N-desmethyl metabolite in healthy volunteers, and evaluate clinically important covariates. Methods A pooledpopulation PK analysis was performed using a non-linear mixed effects approach with plasma concentration data from 346 subjects who received single oral doses of selumetinib 20–75 mg across ten Phase I studies. Absolute bioavailability was determined using intravenous [14C] selumetinib. Results A two compartment, linear model with sequential zero-first order absorption and a lag time for the zero order process was describedselumetinib PK. N-desmethyl metabolite disposition was described by a single compartment with linear elimination without back transformation. The parent-only and joint modelsgenerally adequately described pooled data. For the median subject, not taking interacting drugs, estimates for clearance (CL) and central volume of distribution (V2) for selumetinib in the final joint model were 12.7 L/h and 35.6 L, respectively. Food effects, co-medication with itraconazole (CYP3A4 inhibitor), fluconazole (CYP2C19 inhibitor) and rifampicin (CYP3A4 inducer), and formulation effects were incorporated into the base model a priori. Race and hepatic function were also influential in the PK model. Additional covariates affecting selumetinib disposition identified from covariate analysis were age on V2, bilirubin on CL, and weight on CL and V2. Conclusions Analysis confirmed previous clinical pharmacology studyfindings of drug-drug interactions and food effects, with additional covariates that influence selumetinib and N-desmethyl selumetinib PK identified.Dose modifications based on these additional covariates are not considered necessary.

Zolmitriptan is a serotonin (5-HT) 1B/1D receptor agonist effective for the treatment of migraine. This analysis aimed to develop a population pharmacokinetic (PK) model for zolmitriptan and its active metabolite in adults and adolescents and provide appropriate dosing regimens to be used in clinical trials for children 6–11 years old. The data from a single-dose clinical study of 5.0-mg zolmitriptan nasal spray (ZNS) conducted in adult and adolescent patients with migraine between migraine attacks was applied. Similar plasma concentration profiles of zolmitriptan and its metabolite, 183C91, were observed in adults and adolescents. A 1-compartment model with first-order absorption and first-order elimination reasonably described the zolmitriptan PK. With a portion of elimination of zolmitriptan being treated as the conversion from zolmitriptan to 183C91, the disposition of 183C91 was described by a 1-compartment model with first-order elimination. The estimated typical apparent volume of distribution and clearance of zolmitriptan were 136 L and 121 L/h, respectively, with 56.5% and 42.6% between-subject variability, respectively. Based on the simulation results with the final population PK model, a body weight–based dosing scheme of 5.0 and 2.5 mg ZNS in children greater than and less than 50 kg is recommended to achieve exposures similar to those of the adult and adolescent population administered 5.0 mg ZNS. The recommended doses for children to achieve exposure similar to that observed in adults given 2.5 mg ZNS are 2.5 mg (≥50 kg) and 1.0 mg (15–50 kg). These dosing regimens could be used in future clinical trials.

Naloxegol is a peripherally acting μ-opioid receptor antagonist that was developed for the treatment of opioid-induced constipation. Modeling and simulation of naloxegol efficacy and tolerability informed selection of doses for phase III studies and provided comprehensive dosage recommendations for the naloxegol US package insert.

SummaryWhat is known and objective Lanicemine (AZD6765) is a low-trapping N-methyl-d-aspartate receptor channel blocker that has demonstrated antidepressant efficacy in three of four clinical studies. The aim of this study was to develop a population pharmacokinetic model describing the concentration vs time profile of intravenously administered lanicemine in healthy subjects and patients with major depressive disorder (MDD) and to use the model to evaluate the impact of demographic and clinical factors and concomitant medication on the pharmacokinetics of lanicemine. Methods Data were derived from four studies: two Phase I trials in healthy subjects (studies 8 [NCT01069822] and 13 [NCT00785915]) and two Phase II trials in patients with MDD (studies 1 [NCT00491686] and 9 [NCT00781742]). Population pharmacokinetic analysis was performed by nonlinear mixed-effects modelling. The covariates evaluated within the model included sex, race, age and body weight parameters, clinically relevant laboratory measures, and use of concomitant medications. Goodness-of-fit plots, bootstrap and visual predictive checks were conducted to confirm concordance with observed data. Results and discussion A total of 2531 plasma lanicemine concentrations were available for analysis from 191 healthy subjects and patients with MDD. The pharmacokinetics of lanicemine following intravenous infusion was best described by a two-compartment model with zero-order input and first-order elimination. Mean systemic clearance (CL) was estimated at 9.43 L/h (90% CI 9.12-9.77), central compartment volume of distribution (V1) was 106 L (90% CI 93.7-115), peripheral volume of distribution (V2) was 47.3 (95% CI 39.6-56.6), and intercompartmental clearance (Q) was 75.7 (90% CI 51.8-127). Lean body mass and body surface area had a statistically significant effect on CL and V1, respectively. What is new and conclusions The population pharmacokinetic model developed adequately described the clinical observation of lanicemine in patients with MDD and healthy volunteers. Lean body mass and body surface area were identified as covariates that significantly influence the pharmacokinetics of lanicemine.

Selumetinib (AZD6244, ARRY-142886), a mitogen activated protein kinases (MEK1 and 2) inhibitor, has been granted orphan drug designation for differentiated thyroid cancer. The primary aim of this analysis was to characterize the population pharmacokinetics of selumetinib and its active metabolite N-desmethyl-selumetinib in patients with cancer. Concentration-time data from adult and pediatric clinical trials were pooled to develop a population pharmacokinetic model using a sequential approach where selumetinib and N-desmethyl-selumetinib data were modeled separately. A sequential zero- and first-order absorption with lag time with a two-compartment model for selumetinib and a two-compartment model for N-desmethyl-selumetinib best described the concentration-time data. Intrapatient variability in absorption was higher than interpatient variability. The apparent drug clearance (CL/F) from the central compartment was 13.5 L/hr (RSE 4.9%). Significant covariates for CL/F were age, alanine aminotransferase, and body surface area. This study confirms that flat dosing is appropriate in adults, whereas body-surface area based dosing should be used in pediatric patients.

Naloxegol is a peripherally acting µ-opioid receptor antagonist approved for use as an orally administered tablet (therapeutic doses of 12.5 and 25 mg) for the treatment of opioid-induced constipation. Over a wide dose range (i.e. single supratherapeutic doses up to 1000 mg in healthy volunteers), the pharmacokinetic properties of naloxegol appear to be time- and dose-independent. Naloxegol is rapidly absorbed, with mean time to maximum plasma concentration of

Acalabrutinib, a selective, covalent Bruton tyrosine kinase inhibitor, is a CYP3A substrate and weak CYP3A/CYP2C8 inhibitor. A physiologically‐based pharmacokinetic (PBPK) model was developed for acalabrutinib and its active metabolite ACP‐5862 to predict potential drug–drug interactions (DDIs). The model indicated acalabrutinib would not perpetrate a CYP2C8 or CYP3A DDI with the sensitive CYP substrates rosiglitazone or midazolam, respectively. The model reasonably predicted clinically observed acalabrutinib DDI with the CYP3A perpetrators itraconazole (4.80‐fold vs. 5.21‐fold observed) and rifampicin (0.21‐fold vs. 0.23‐fold observed). An increase of two to threefold acalabrutinib area under the curve was predicted for coadministration with moderate CYP3A inhibitors. When both the parent drug and active metabolite (total active components) were considered, the magnitude of the CYP3A DDI was much less significant. PBPK dosing recommendations for DDIs should consider the magnitude of the parent drug excursion, relative to safe parent drug exposures, along with the excursion of total active components to best enable safe and adequate pharmacodynamic coverage.

Ceftazidime is a widely used β-lactam antibiotic and almost entirely excreted via glomerular filtration in kidney. The objective of this analysis was to assess the ability of physiologically based pharmacokinetic (PBPK) model to predict ceftazidime exposure in healthy volunteers and subjects with renal impairment. A full PBPK model of ceftazidime was developed using physiochemical properties and clinical data. The total clearance of 115 mL/min and renal clearance of 100 mL/min were obtained from ceftazidime package insert. Healthy and chronic kidney disease (CKD) populations were applied for sampling of virtual subjects. The established PBPK model predicted mean plasma AUCinf were 138.5 ± 19.6, 230.7 ± 22.2, 369.3 ± 53.1 and 561.8 ± 92.4 h µg/mL in healthy, mild, moderate and severe renal impairment subjects, respectively, after administration of 1 g ceftazidime intravenous bolus dose. The predicted values were in close agreement with the weighted mean of the five reported clinical studies. The exposure was slightly under predicted in subjects with severely impaired renal function, but still within 1.5-fold range. The concentration-time profiles of ceftazidime were also well captured in healthy volunteers and subjects with renal impairment. The developed PBPK model along with systems pharmacokinetics (PK) (renal impaired populations) well predicted the ceftazidime exposure. PBPK models verified with clinical study in healthy volunteers could be potentially applied to predict PK and recommend dose adjustment for CKD patients.

Olaparib is a first-in-class potent oral poly(ADP-ribose) polymerase inhibitor. The aims of this analysis were to establish an integrated population pharmacokinetic (PK) model of olaparib in patients with solid tumors and to bridge the PK of olaparib between capsule and tablet formulations. The population PK model was developed using plasma concentration data from 659 patients in 11 phase I, II, and III studies of olaparib tablets/capsules monotherapy. Relative bioavailability between the tablet and capsule formulations was estimated and the relative exposure between olaparib tablet and capsule therapeutic doses was further assessed. The concentration–time profile was described using a two-compartment model with sequential zero- and first-order absorption and first-order elimination for both capsules and tablets with different absorption parameters. Multiple-dose clearance compared with single-dose clearance was reduced by approximately 15% (auto-inhibition). Disease severity had an impact on olaparib clearance, and tablet strength had an impact on Ka. The olaparib geometric mean area under the curve (AUC) and maximal concentration (Cmax) following a single 300 mg tablet were 42.1 μg h/mL and 5.8 μg/mL, respectively, and the steady-state geometric mean AUC and Cmax following a 300 mg tablet twice daily were 49.0 μg h/mL and 7.7 μg/mL, respectively. The relative exposure (AUC) of the 300 mg tablet formulation is 13% higher than the 400 mg capsule formulation. This analysis bridged the olaparib capsule and tablet formulation PK and provided key assessment to support the approval of the olaparib tablet formulation in patients with ovarian cancer, regardless of their BRCA mutation status.

Danvatirsen is a Generation 2.5 antisense oligonucleotide under clinical development. Population PK modelling was conducted using data from 3 available danvatirsen Phase I/II studies in oncology patients to investigate the impact of flat dosing on exposure compared to ideal body weight-based dosing. A total of 126 patients who received danvatirsen doses ranging from 1 to 4 mg/kg as monotherapy or in combination with durvalumab, most at 3 mg/kg (n = 70), was used in the danvatirsen population PK analysis. A 2-compartment model with linear elimination described the data well. Covariate analysis revealed ideal body weight was not a significant covariate on the PK of danvatirsen; nor was age, sex or race. The model-based simulation suggested that steady state weekly AUC and Cmax were very similar between 3 mg/kg and 200 mg flat dosing (geometric mean of AUC: 62.5 vs. 63.4 mg h/L and Cmax: 26.2 vs. 26.5 mg/L for two dose groups) with slightly less overall between-subject variability in the flat dosing regimen. The switch to flat dosing was approved by multiple regulatory agencies, including FDA, EMA, PMDA and ANSM. Several ongoing studies have been evaluating flat dosing. Interim analysis from an ongoing study (D5660C00016, NCT03421353) has shown the observed steady state concentration from 200 mg flat dose is in agreement with the model predictions. The population PK model could be further utilized in subsequent exposure-response efficacy and safety modelling.

Aztreonam is a monocyclic β-lactam antibiotic often used to treat infections caused by Enterobacteriaceae or Pseudomonas aeruginosa. Despite the long history of clinical use, population pharmacokinetic modeling of aztreonam in renally impaired patients is not yet available. The aims of this study were to assess the impact of renal impairment on aztreonam exposure and to evaluate dosing regimens for patients with renal impairment. A population model describing aztreonam pharmacokinetics following intravenous administration was developed using plasma concentrations from 42 healthy volunteers and renally impaired patients from 2 clinical studies. The final pharmacokinetic model was used to predict aztreonam plasma concentrations and evaluate the probability of pharmacodynamic target attainment (PTA) in patients with different levels of renal function. A 2-compartment model with first-order elimination adequately described aztreonam pharmacokinetics. The population mean estimates of aztreonam clearance, intercompartmental clearance, volume of distribution of the central compartment, and volume of distribution of the peripheral compartment were 4.93 L/h, 9.26 L/h, 7.43 L, and 6.44 L, respectively. Creatinine clearance and body weight were the most significant variables to explain patient variability in aztreonam clearance and volume of distribution, respectively. Simulations using the final pharmacokinetic model resulted in a clinical susceptibility break point of 4 and 8 mg/L, respectively, based on the clinical use of 1- and 2-g loading doses with the same or reduced maintenance dose every 8 hours for various renal deficiency patients. The population pharmacokinetic modeling and PTA estimation support adequate PTAs (>90% PTA) from the aztreonam label for dose adjustment of aztreonam in patients with moderate and severe renal impairment.

Predictive performance of physiologically based pharmacokinetic (PBPK) and population pharmacokinetic (PopPK) models of drugs predominantly eliminated through kidney in the pediatric population was evaluated. After optimization using adult clinical data, the verified PBPK models can predict 33 of 34 drug clearance within twofold of the observed values in children 1 month and older. More specifically, 10 of 11 of predicted clearance values were within 1.5-fold of those observed in children between 1 month and 2 years old. The PopPK approach also predicted 19 of 21 drug clearance within twofold of the observed values in children. In summary, our analysis demonstrated both PBPK and PopPK adult models, after verification with additional adult pharmacokinetic (PK) studies and incorporation of known ontogeny of renal filtration, could be applied for dosing regimen recommendation in children 1 month and older for renally eliminated drugs in a first-in-pediatric study.

Background: Estrogen receptor positive (ER+) breast cancer is routinely treated with endocrine therapies targeting the ER axis. However, primary and secondary resistance ultimately limits the use of these agents. Fulvestrant (FULV) is the first-in-class selective ER degrader (SERD) clinically effective in patients with ER+ breast cancer, both naïve and resistant to tamoxifen and aromatase inhibitors. FULV has low oral bioavailability, and its dose-dependent pharmacodynamic (PD) activity and clinical efficacy is limited by the currently approved maximal feasible dose (MFD) of 500 mg, which is administered monthly as two intramuscular injections. AZD9496 is an orally bioavailable, nonsteroidal, selective and potent degrader and antagonist of ER in preclinical models. This pre-surgical, window of opportunity study (NCT03236974) compared PD changes and the PD/pharmacokinetic (PK) relationships of AZD9496 with FULV in patients with newly diagnosed ER+ HER2- breast cancer awaiting curative intent surgery.Methods: In this open-label, multicenter study, patients were randomized 1:1 to receive oral AZD9496 250 mg BID from Day 1 for 5-14 days or FULV 500 mg administered intramuscularly on Day 1 only. On-treatment image-guided core tumor biopsies were taken between Days 5 and 14. The primary objective was to compare the effects of AZD9496 and FULV on ER expression in tumor tissue using pre-dose biopsies as baseline. Secondary objectives were changes in progesterone receptor (PR) and Ki-67 biomarkers, AZD9496 and FULV plasma concentrations during treatment, and safety. Immunohistochemistry was used to determine ER and PR H-scores, and Ki-67 index, and treatment effects were compared using an analysis of covariance model. Blood samples for PK analysis were taken at on-treatment biopsy and 1-2 hours afterwards. Adverse events (AEs) were monitored from screening through to a follow-up visit 28 days after the last study dose.Results: Of the 49 women enrolled, 46 received treatment (AZD9496 n=22; FULV n=24) and of these, 35 paired biopsies were evaluable (AZD9496 n=15; FULV n=20). The least square mean estimate for the reduction in ER H-score after AZD9496 treatment was 24% (80% CI: 34.4, 14.3), and after FULV treatment was 36% (44.9, 27.7), with a least square mean difference between AZD9496 and FULV of 12% (p=0.86). AZD9496 was not superior to FULV in terms of ER modulation at the tested dose. AZD9496 also reduced PR H-scores and Ki-67 levels from baseline (by 33.3% and 39.9%, respectively). These effects were not statistically superior to FULV at the tested dose (PR: -68.7%, p=0.97; Ki 67: 75.4%, p=0.98).Plasma exposure of AZD9496 (AUC -40%, Cmax -25%) was lower than predicted based on PK data from the previous phase 1 study, whereas FULV exposure was consistent with historical data. No clear exposure-response relationship for plasma concentration at biopsy and PD markers for AZD9496 or FULV were observed.The median treatment duration of AZD9496 was 9.5 days (range: 6-15), and the relative dose intensity was 100% (range: 90-125); no patients discontinued AZD9496. AZD9496 and FULV were both well tolerated, and no new safety findings were identified. No grade ≥3 toxicities or serious AEs occurred. Conclusion: AZD9496 250 mg BID reduced ER, PR and Ki-67 expression, and as such, is the first pre surgical study to demonstrate an oral SERD impacting its key biological targets. These reductions were not superior to the FULV clinically approved dose, which performed as expected based on historical data. Pre-surgical studies represent an important method to test the proof of mechanism of novel SERDs early in clinical development. Citation Format: John FR Robertson, Abigail Evans, Stephan Henschen, Cliona Kirwan, Ali Jahan, Laura Kenny, J. Michael Dixon, Peter Schmid, Ashutosh Kothari, Omar Mohamed, Peter A Fasching, Kwok-Leung Cheung, Rachel Wuerstlein, Danielle Carroll, Teresa Klinowska, Justin PO Lindemann, Alexander MacDonald, Richard Mather, Rhiannon Maudsley, Michele Moschetta, Myria Nikolaou, Martine P Roudier, Tinnu Sarvotham, Gaia Schiavon, Diansong Zhou, Li Zhou, Nadia Harbeck. A pre-surgical, window of opportunity study comparing the novel oral SERD AZD9496 with fulvestrant in patients with newly diagnosed ER+ HER2- primary breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-04-01.

Understanding the influence of ethnicity on drug exposure is key to patient safety and could minimize repetitive clinical studies. This analysis aimed to evaluate the ability of physiologically-based pharmacokinetic modelling to predict exposure of CYP2C19 substrates (lansoprazole, (es)citalopram, voriconazole) across Caucasian and East Asian populations. CYP2C19 abundance levels in Japanese and Chinese populations have been re-assessed based on clinical evidence. Model performance in each population was evaluated by predicted-over-observed AUC ratios and comparison of observed data with simulated plasma concentration profiles. Exposures in 84.4% (76 out of 90) of the clinical studies were predicted within 1.5-fold of observed values. The reported concentration-time profiles were well-captured within the 90% prediction intervals. With specified CYP2C19 phenotype, PBPK modelling is capable to predict systemic exposure of drugs largely metabolized by CYP2C19 in different ethnic populations. This study demonstrated PBPK modelling can be applied to assess genotype-dependent exposure difference across ethnicities.

Efficacy of ceftaroline fosamil, the prodrug of the active metabolite ceftaroline, was demonstrated in a phase 3 study of hospitalized Asian patients with Pneumonia Outcomes Research Team (PORT) risk class III-IV community-acquired pneumonia (NCT01371838). The objectives of the current analysis were to expand an existing ceftaroline and ceftaroline fosamil population pharmacokinetic (PK) model with data from this phase 3 study and a phase 1 study (NCT01458743) assessing ceftaroline PK in healthy Chinese volunteers and to evaluate the probability of PK/pharmacodynamic (PK/PD) target attainment (PTA) in Asian patients with community-acquired pneumonia (CAP) treated with ceftaroline fosamil. The ceftaroline plasma concentration-time course was simulated for 5000 Asian patients with CAP for different renal function subgroups using the final model. PTA was calculated for Streptococcus pneumoniae, Staphylococcus aureus, and non-extended-spectrum β-lactamase-producing Enterobacteriaceae. PTA was also evaluated for ceftaroline MIC90 values of isolates collected from Asia-Pacific surveillance studies (2012-2014) and for EUCAST and FDA/CLSI ceftaroline susceptibility break points. The final model reasonably described the ceftaroline PK. Race was not found to be a significant covariate impacting ceftaroline PK, suggesting similar ceftaroline PK in Asian and Western populations when corrected for body weight. High PTAs (90%-100%) were predicted for Asian patients with CAP treated with ceftaroline fosamil, covering MIC90 values of target CAP pathogens from the region. Similarly, >90% PTAs were predicted at EUCAST and FDA/CLSI clinical break points for these pathogens. These results support the use of the ceftaroline fosamil dosing regimens approved in Europe and the United States in Asian patients with PORT III-IV CAP.

Objectives To describe the pharmacokinetic/pharmacodynamic (PK/PD) modelling and microbiological data that were used to support the recent European approval of ceftaroline fosamil 600 mg q8h by 2 h intravenous (iv) infusion for patients with complicated skin and soft tissue infections (cSSTIs) caused by Staphylococcus aureus with ceftaroline MICs of 2 or 4 mg/L, and the associated EUCAST MIC breakpoint update for q8h dosing (intermediate = 2 mg/L and resistant >2 mg/L). Methods A population PK model for ceftaroline and ceftaroline fosamil was developed using PK data from 21 clinical studies. The final model was used to simulate PTA in patients with cSSTI receiving ceftaroline fosamil 600 mg q12h by 1 h iv infusion or 600 mg q8h by 2 h iv infusion. PTA was calculated by MIC for S. aureus PK/PD targets derived from preclinical studies (27% fT>MIC for stasis, 31% fT>MIC for 1 log10 kill and 35% fT>MIC for 2 log10 kill) and compared with S. aureus ceftaroline MIC distributions from a 2013 global surveillance study. Results The final population PK model based on 951 subjects adequately described ceftaroline and ceftaroline fosamil PK. High PTA (>90%) was predicted for the ceftaroline fosamil 600 mg q12h dosage regimen against S. aureus isolates with ceftaroline MICs ≤2 mg/L. Greater than 90% PTA was predicted for the ceftaroline fosamil 600 mg q8h dosage regimen against S. aureus with ceftaroline MICs ≤4 mg/L. Conclusions The approved ceftaroline fosamil dosage regimens for adults and adolescents with cSSTI achieve high PTA against S. aureus at the associated EUCAST breakpoints.

AZD3241 is a potent and selective myeloperoxidase inhibitor potentially for the treatment of a number of neurodegenerative disorders, including multiple system atrophy (MSA). The objectives of this work were to develop a population pharmacokinetic (PopPK) model for AZD3241 and to investigate the correlation between AZD3241 exposure and myeloperoxidase inhibition. The PopPK model was developed using AZD3241 data from one phase 1 study in healthy subjects and one phase 2 study in patients with MSA. A one-compartment model incorporating a gallbladder compartment for enterohepatic circulation, sequential zero-first order absorption, and first-order elimination adequately described the AZD3241 concentration profiles. The apparent clearance and central volume of distribution were 63.1 L/h (interindividual variability: 34.8%) and 121.9 L (interindividual variability: 44.0%), respectively. The enterohepatic circulation model reasonably captured the second peak of AZD3241, and high-fat food increased the absorption rate by 69%. A linear regression model was applied to describe the relationship between AZD3241 exposure and percentage change from baseline in myeloperoxidase-specific activity. The developed PopPK model was consistent with known pharmacokinetic characteristics of AZD3241. This model can be used to estimate AZD3241 exposure in patients with MSA and could be applied to future pharmacokinetic-pharmacodynamic analyses of AZD3241 in clinical development.

4-{(R)-(3-Aminophenyl)[4-(4-fluorobenzyl)-piperazin-1-yl]methyl}-N,N-diethylbenzamide (AZD2327) is a highly potent and selective agonist of the δ-opioid receptor. AZD2327 and N-deethylated AZD2327 (M1) are substrates of cytochrome P450 3A (CYP3A4) and comprise a complex multiple inhibitory system that causes competitive and time-dependent inhibition of CYP3A4. The aim of the current work was to develop a physiologically based pharmacokinetic (PBPK) model to predict quantitatively the magnitude of CYP3A4 mediated drug-drug interaction with midazolam as the substrate. Integrating in silico, in vitro and in vivo PK data, a PBPK model was successfully developed to simulate the clinical accumulation of AZD2327 and its primary metabolite. The inhibition of CYP3A4 by AZD2327, using midazolam as a probe drug, was reasonably predicted. The predicted maximum concentration (Cmax) and area under the concentration-time curve (AUC) for midazolam were increased by 1.75 and 2.45-fold, respectively, after multiple dosing of AZD2327, indicating no or low risk for clinically relevant drug-drug interactions (DDI). These results are in agreement with those obtained in a clinical trial with a 1.4 and 1.5-fold increase in Cmax and AUC of midazolam, respectively. In conclusion, this model simulated DDI with less than a two-fold error, indicating that complex clinical DDI associated with multiple mechanisms, pathways and inhibitors (parent and metabolite) can be predicted using a well-developed PBPK model.

A population model describing quetiapine pharmacokinetics (PK) in Western and Chinese patients following oral administration of immediate-release (IR) and extended-release (XR) formulations was developed using plasma concentrations in 127 patients from 5 studies with quetiapine IR and/or XR in Western patients and 1 study with quetiapine XR in Chinese patients. A 1-compartmental model with first-order absorption and first-order elimination adequately described the quetiapine PK. The typical apparent volume of distribution and elimination rate constant of quetiapine were 574 L and 0.12 h(-) (1) , respectively. The estimated population absorption rate constants were 1.46 and 0.10 h(-1) for quetiapine IR and XR, respectively. Covariate analysis revealed that race was not a significant covariate influencing the PK of quetiapine. Simulation conducted with the final quetiapine population PK model predicted that the administration of a 200-mg twice-daily dose of quetiapine IR in Chinese patients would achieve a steady-state AUC (AUCss ) ± standard deviation of 3087 ± 1480 ng · h/mL, which is in close agreement with the reported value (3538 ± 1728 ng · h/mL). The model also predicted that once-daily administration of 300 mg quetiapine IR or XR would achieve similar exposure in terms of AUCss in Chinese patients.

The objectives of the present study were to evaluate safety and tolerability as well as the effects of multiple doses of lanicemine on the pharmacokinetics of a CYP3A substrate, midazolam. A total of 46 healthy volunteers were enrolled in the open-label, fixed-sequence, nonrandomized study. All volunteers received an oral dose of 5 mg of midazolam alone or after 6 days of 150 mg daily intravenous infusion of lanicemine. Lanicemine reached a plasma Cmax of 1.51 μg/mL after 150 mg daily dosing to steady state. The geometric mean CL, Vss, and t1/2 of lanicemine were 8.1 L/h, 122.0 L, and 10.4 hours, respectively. The geometric least-squares mean ratios and 90% confidence intervals for midazolam AUC0- ∞ , and Cmax were within the 80% to 125% limits when lanicemine plus midazolam treatment was compared with midazolam alone, demonstrating that daily dosing with 150 mg of lanicemine for 6 days had no effect on CYP3A activity. Comprehensive physiologically based pharmacokinetic modeling using in vitro and in silico findings also indicated lanicemine would have little impact on the pharmacokinetics of CYP3A substrate, such as midazolam. In addition, lanicemine and midazolam administered alone or in combination were generally safe and well tolerated.

Gefitinib is a selective inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase and is used for the treatment of non-small-cell lung cancer (NSCLC) with activating EGFR mutations. Gefitinib is metabolized by CYP2D6 and CYP3A4. This analysis compared the systemic exposure of gefitinib after oral administration in CYP2D6 ultrarapid metabolizers (UM) vs extensive metabolizers (EM). Physiologically based pharmacokinetic (PBPK) modeling was conducted using a population-based simulator. The model was calibrated using itraconazole-gefitinib clinical drug-drug interaction data and validated with gefitinib data in CYP2D6 EM vs poor metabolizers (PM). System components of the PBPK model were evaluated using published clinical metoprolol pharmacokinetic data in CYP2D6 UM, EM, and PM. Our PBPK model predicted a gefitinib geometric least-squares mean area under the plasma concentration-time curve (AUC) from time 0 to 264 hours (AUC(0-264) ) ratio in the presence vs absence of itraconazole of 1.85, similar to the ratio of 1.78 from clinical study data. Predicted and observed metoprolol geometric least-squares mean AUC(0-24) ratios in UM vs EM were also similar (0.46 and 0.55, respectively), suggesting that system components related to CYP2D6 in the PBPK model were properly established. In addition, the PBPK model also captured gefitinib pharmacokinetic profiles in CYP2D6 polymorphic populations. The final PBPK model predicted a decrease in gefitinib AUC of ∼39% in CYP2D6 UM vs EM. Such changes in exposure will have limited impact as the reduced exposure is still above gefitinib's in vitro IC90 for EGFR activating mutations in NSCLC patients.

Naloxegol is approved for the treatment of opioid‐induced constipation (OIC) in adults with chronic noncancer pain. Population exposure‐response models were developed using data from a phase II study comprising 185 adults with OIC. The weekly probability of response defined as having ≥3/week spontaneous bowel movements (SBMs) and ≥1 SBM/week increase over baseline was characterized by a longitudinal mixed‐effects logistic regression dose‐response model, and the probability of time to discontinuation was modeled with a Weibull distribution function. The predicted probability of SBM in a given week increased with increasing naloxegol dose. The model predicted that 12.5, 25, and 37.5 mg doses would produce median response rates of 40%, 50%, and 60%, and dropout rates of 13.3%, 16.7%, and 23.3%, respectively. The large overlap of predicted difference of the response rate between placebo and the 25 or 37.5 mg doses suggested little utility of using a 37.5 mg dose in phase III studies.

Zolmitriptan is a serotonin (5-HT)

Itopride, a substrate of FMO3, has been used for the symptomatic treatment of various gastrointestinal disorders. Physiologically based pharmacokinetic (PBPK) modeling was applied to evaluate the impact of FMO3 polymorphism on itopride pharmacokinetics (PK). The Asian populations within the Simcyp simulator were updated to incorporate information on the frequency, activity and abundance of FMO3 enzyme with different phenotypes. A meta-analysis of relative enzyme activities suggested that FMO3 activity in subjects with homozygous Glu158Lys and Glu308Gly mutations (Lys158 and Gly308) in both alleles is ~47% lower than those carrying two wild-type FMO3 alleles. Individuals with homozygous Lys158 and Gly308 mutations account for about 5% of the total population in Asian populations. A CLint of 9 μl/min/pmol was optimised for itopride via a retrograde approach as human liver microsomal results would under-predict its clearance by ~7.9-fold. The developed itopride PBPK model was first verified with three additional clinical studies in Korean and Japanese subjects resulting in a predicted clearance of 52 to 69 l/h, which was comparable to those observed (55 to 88 l/h). The model was then applied to predict plasma concentration-time profiles of itopride in Chinese subjects with wild type or homozygous Lys158 and Gly308 FMO3 genotypes. The ratios of predicted to observed AUC of itopride in subjects with each genotype were 1.23 and 0.94, respectively. In addition, the results also suggested that for FMO3 metabolised drugs with a safety margin of 2 or more, proactive genotyping FMO3 to exclude subjects with homozygous Lys158/Gly308 alleles may not be necessary.