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Background Exposure–response analyses were conducted to explore the relationship between selected efficacy and safety endpoints and serum phosphate (PO4) concentrations, a potential biomarker of efficacy and safety, in locally advanced or metastatic urothelial carcinoma patients with FGFR alterations treated with erdafitinib. Methods Data from two dosing regimens of erdafitinib in a phase 2 study (NCT02365597), 6 and 8-mg/day with provision for pharmacodynamically guided titration per serum PO4 levels, were analyzed using Cox proportional hazard or logistic regression models. Efficacy endpoints were overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Safety endpoints were adverse events typical for FGFR inhibitors. Results Exposure-efficacy analyses on 156 patients (6-mg = 68; 8-mg = 88) showed that patients with higher serum PO4 levels within the first 6 weeks showed better OS (hazard ratio 0.57 [95% CI 0.46–0.72] per mg/dL of PO4; p = 0.01), PFS (hazard ratio 0.80 [0.67–0.94] per mg/dL of PO4; p = 0.01), and ORR (odds ratio 1.38 [1.02–1.86] per mg/dL of PO4; p = 0.04). Exposure-safety analyses on 177 patients (6-mg = 78; 8-mg = 99) showed that the incidence of selected adverse events associated with on-target off-tumor effects significantly rose with higher PO4. Conclusions The exploratory relationship between serum PO4 levels and efficacy/safety outcomes supported the use of pharmacodynamically guided dose titration to optimize erdafitinib’s therapeutic benefit/risk ratio. Clinical trial registration number NCT02365597.

A population pharmacokinetic (PK)-pharmacodynamic (PD) model was developed using data from 345 patients with cancer. The population PK-PD model evaluated the effect of erdafitinib total and free plasma concentrations on serum phosphate concentrations after once-daily oral continuous (0.5-12 mg) and intermittent (10-12 mg for 7 days on/7 days off) dosing, and investigated the potential covariates affecting erdafitinib-related changes in serum phosphate levels. Phosphate is used as a biomarker for erdafitinib's efficacy and safety: increases in serum phosphate were observed after dosing with erdafitinib, which were associated with fibroblast growth factor receptor target engagement via inhibition of renal fibroblast growth factor 23-mediated signaling. PK-PD model-based simulations were performed to assess the approved PD-guided dosing algorithm of erdafitinib (8 mg once-daily continuous dosing, with up-titration to 9 mg based on phosphate levels [5.5 mg/dl] and tolerability at 14-21 days of treatment). The serum phosphate concentrations increased after the first dose and reached near maximal level after 14 days of continuous treatment. Serum phosphate increased with erdafitinib free drug concentrations: doubling the free concentration resulted in a 1.8-fold increase in drug-related phosphate changes. Dose adjustment after at least 14 days of dosing was supported by achievement of95% maximal serum phosphate concentration. The peak-to-trough fluctuation within a dosing interval was limited for serum phosphate concentrations (5.68-5.65 mg/dl on Day 14), supporting phosphate monitoring at any time relative to dosing. Baseline phosphate was higher in women, otherwise, none of the investigated covariate-parameter relationships were considered clinically relevant. Simulations suggest that the starting dose of 8-mg with up-titration to 9-mg on Days 14-21 maximized the number of patients within the target serum phosphate concentrations (5.5-7 mg/dl) while limiting the number of treatment interruptions. The findings from the PK-PD model provided a detailed understanding of the erdafitinib concentration-related phosphate changes over time, which supports erdafitinib's dosing algorithm.

A population pharmacokinetic (PK) model was developed using data pooled from 6 clinical studies (3 in healthy volunteers and 3 in cancer patients) to characterize total and free plasma concentrations of erdafitinib following single- and multiple-dose administration, to understand clinically relevant covariates, and to quantify the inter- and intraindividual variability in erdafitinib PK. An open, linear, 3-compartment disposition model with first-order absorption and a lag time was used to describe the PK profile of total and free erdafitinib plasma concentrations. The PK of erdafitinib were linear and time independent. After oral administration, erdafitinib was rapidly absorbed, with a time to maximum concentration between 2 and 4 hours. In patients, erdafitinib total apparent oral clearance was 0.200 L/h (median free fraction = 0.24%), and the effective terminal half-life of total drug was 76.4 hours. Interindividual variability in PK parameters was moderate for oral clearance and central volume of distribution, and large for absorption rate and peripheral volume of distribution. Sex and renal function were significant covariates on free oral clearance, while weight, sex, and α1 -acid-glycoprotein were significant on oral central volume of distribution. Age, race, and mild hepatic impairment were not significant covariates of erdafitinib exposure. Given that the magnitude of the covariate effects were within 25% of reference values and that the recommended dosing regimen of erdafitinib comprises individual dose up-titrations and reductions based on presence or absence of toxicities, the clinical relevance of the investigated covariates is expected to be limited, and no dose adjustments are warranted.

To characterize the effect of erdafitinib on electrocardiogram (ECG) parameters and the relationship between erdafitinib plasma concentrations and QTc interval changes in patients with advanced or refractory solid tumors. Triplicate ECGs and continuous 12-lead Holter data were collected in the dose escalation part (Part 1) of the first-in-human study, with doses ranging from 0.5 to 12 mg. Triplicate ECG monitoring continued in Parts 2–4 where 2 dose regimens selected from Part 1 were expanded in prespecified tumor types. Analyses of ECG data included central tendency analyses, identification of categorical outliers and morphological assessment. A concentration–QTc analysis was conducted using a linear mixed-effect model based on extracted time matching Holter data. Central tendency, categorical outlier, and ECG morphologic analyses from 187 patients revealed no clinically significant effect of erdafitinib on heart rate, atrioventricular conduction or cardiac depolarization (PR and QRS), and no effect on cardiac repolarization (QTc). Concentration–QTc analysis from 62 patients indicated that the slopes of relationship between total and free erdafitinib plasma concentrations and QTcI (mean exponent of 0.395) were estimated as − 0.00269 ms/(ng/mL) and − 1.138 ms/(ng/mL), respectively. The predicted change in QTcI at the observed geometric mean of total and free concentration at the highest therapeutic erdafitinib dose (9 mg daily) was

Aims Pregnant women can be exposed to numerous drugs during the gestational period. For obvious ethical reasons, in vivo studies of fetal exposure to drugs are limited. Information about the transplacental transfer of drugs prior to their administration to pregnant women would be highly useful. In the present study, a novel approach was developed quantitatively predict or to predict the fetal exposure to drugs administered to the mother quantitatively. Methods Transplacental parameters estimated from ex vivo human placenta perfusion experiments were implemented in pregnancy-physiologically based pharmacokinetic (p-PBPK) models in order to predict fetal PK. Thereafter, fetal PK profiles for two antiretroviral drugs, tenofovir (TFV) and emtricitabine (FTC) were simulated. These predictions were then compared to observed cord blood concentrations, to validate these models. Results Parameters obtained from the ex vivo experiments enabled a good prediction of observed cord blood concentrations without additional a scaling factor. Moreover, a sensitivity analysis showed that fetal predictions were sensitive to changes in transplacental parameters values obtained ex vivo. Conclusion The integration of ex vivo human placental perfusion parameters in a p-PBPK model should be a promising new approach for predicting human fetal exposure to xenobiotics.

The aim of this study was to characterize the pharmacokinetic drug–drug interaction (DDI) between simeprevir (NS3/4A protease inhibitor) and odalasvir (NS5A inhibitor) after oral administration to support the design and dose selection of clinical studies with this combination for the treatment of chronic hepatitis C infection (HCV). Simeprevir and odalasvir plasma concentrations from 30 healthy subjects receiving these drugs in monotherapy as well as in combination were pooled and analyzed using a population pharmacokinetic modeling approach. Previous pharmacokinetic models developed to characterize the pharmacokinetics for each drug were used as starting point. The dual effect of simeprevir and odalasvir on their pharmacokinetic parameters was explored. Simulations were performed to assess the impact of the DDI on exposure parameters. In presence of odalasvir, the relative bioavailability of simeprevir increased by 26% and the apparent clearance was reduced following competitive inhibition depending on odalasvir plasma concentrations, with an inhibitory constant (Ki) estimated to be 1610 ng/mL. The apparent odalasvir clearance was reduced by simeprevir plasma concentrations following an Imax model, characterized by a maximum inhibitory effect of 46.7% and an IC50 of 257 ng/mL. Model-based simulations indicated that both Cmax and AUC24h increased for both drugs, when co-administered. The pharmacokinetic model adequately describes the time course of plasma concentrations and their variability when simeprevir and/or odalasvir were orally administered. This model can be used as a first step to predict the exposures of concomitant administration of simeprevir and odalasvir in HCV-infected subjects. Data from study AL355-602 (NCT02512562) were used for this analysis.

The aim of the current study was to characterize the time course of plasma concentrations of AL-335 and its main metabolites (ALS-022399 and ALS-022227) after oral administration in healthy and hepatitis C virus (HCV)-infected subjects, in monotherapy as well as in combination with simeprevir and/or odalasvir. AL-335, ALS-022399, and ALS-022227 plasma concentrations from subjects receiving 800 mg of AL-335 orally once daily (qd) as monotherapy or in combination were pooled and analyzed using a nonlinear mixed effect modeling approach. The typical values (between subject variability) of AL-335 and ALS-022399 apparent linear clearances were 3300 L/h (33.9%) and 1910 L/h (30.0%), respectively. ALS-022227 elimination was characterized as a nonlinear process, with typical values of Vmax,ALS-022227 and Km,ALS-022227 estimated to be 84,799 ng/h (14.9%) and 450.2 ng/mL, respectively. AL-335 and ALS-022399 plasma concentrations were increased more than 2-fold in presence of simeprevir and/or odalasvir, while the effect on ALS-022227 plasma concentrations was limited. The effect of simeprevir and/or odalasvir might be explained by their capacity to inhibit P-glycoprotein. Internal evaluation confirmed that the population pharmacokinetic model developed was deemed appropriate to describe the time course of AL-335, ALS-022399, and ALS-022227 plasma concentrations and their associated variability in both healthy and HCV-infected subjects, as well as the interaction effect of simeprevir and/or odalasvir over AL-335 and its metabolites in healthy subjects. This model can be used as a starting point to evaluate drug-drug interaction processes in HCV-infected patients and support the development of a direct-acting antiviral (DAA) combination.

Aim Physiological changes during pregnancy can affect drug disposition. Anticipating these changes will help to maximize drug efficacy and safety in pregnant women. Our objective was to determine if physiologically-based pharmacokinetics (PBPK) can accurately predict changes in the disposition of renally excreted antiretroviral drugs during pregnancy. Methods Whole body PBPK models were developed for three renally excreted antiretroviral drugs, tenofovir (TFV), emtricitabine (FTC) and lamivudine (3TC). To assess the impact of pregnancy on PK, time-varying pregnancy-related physiological parameters available within the p-PBPK Simcyp® software package were used. Renal clearance during pregnancy followed glomerular filtration changes with or without alterations in secretion. PK profiles were simulated and compared with observed data, i.e. area under the curves (AUC), peak plasma concentrations (Cmax) and oral clearances (CL/F). Results PBPK models successfully predicted TFV, FTC and 3TC disposition for non-pregnant and pregnant populations. Both renal secretion and filtration changed during pregnancy. Changes in renal clearance secretion were related to changes in renal plasma flow. The maximum clearance increases were approximately 30% (TFV 33%, FTC 31%, 3TC 29%). Conclusions Pregnancy PBPK models are useful tools to quantify a priori the drug exposure changes during pregnancy for renally excreted drugs. These models can be applied to evaluate alternative dosing regimens to optimize drug therapy during pregnancy.

The aims of this study were to describe the blood plasma (BP) and seminal plasma (SP) pharmacokinetics of tenofovir (TFV) in HIV-1-infected men, to assess the role of genetic polymorphism in the variability of TFV transfer into the male genital tract, and to evaluate the impact of TFV SP exposure on seminal plasma HIV load (spVL). Men from the Evarist-ANRS EP 49 study treated with TFV as part of their antiretroviral therapy were included in the study. A total of 248 and 217 TFV BP and SP concentrations from 129 men were available for the analysis. For pharmacogenetic assessment, a total of 121 single nucleotide polymorphisms (SNP) were genotyped. Data were analyzed using a nonlinear mixed-effects modeling approach. TFV pharmacokinetics were best described by a two-compartment model for BP and by an effect compartment with different input and output constants for SP. TFV exposures (area under the concentration-time curve from 0 to 24 h [AUC 0–24 ]) were higher in SP than in BP (median AUC 0–24 , 7.01 versus 2.97 mg · liter −1 · h, respectively). The median (range) SP-to-BP AUC 0–24 ratio was 2.24 (0.53 to 34.13). After correction for multiple testing, none of the SNPs were significantly associated with the TFV transfer rate constant. The impact of the TFV SP AUC 0–24 or TFV SP-to-BP AUC 0–24 ratio on spVL was not significant ( P = 0.808 and 0.768, respectively). This is the first population model describing TFV pharmacokinetics in the male genital tract. TFV SP concentrations were higher than BP concentrations. Despite TFV SP exposures being higher than BP exposures, an spVL was detectable for 12.2% of the men.

Aims The aims were to describe emtricitabine (FTC) pharmacokinetics in a large population of pregnant women during the different trimesters of pregnancy, and to explain FTC pharmacokinetic variability during pregnancy. Methods FTC plasma concentrations were measured in 103 non-pregnant and 83 pregnant women, including women in the different trimesters of pregnancy and on the day of delivery. A total of 457 plasma concentrations were available for analysis. A population pharmacokinetic model was developed with Monolix 4.1.3. Results FTC pharmacokinetics was best described by a two compartment model. The effect of creatinine clearance on apparent elimination clearance (CL/F) was significant. CL/F in pregnant women was significantly higher compared with non-pregnant women (geometric mean 24.1 vs 20.5 l h−1, P

Aims The main goal of the study was to describe the pharmacokinetics of maternal zidovudine (ZDV) administration during pregnancy and labour and to evaluate their impact on fetal concentrations and exposures. Methods A total of 195 HIV-infected pregnant and non-pregnant women aged 16–59 years were included and 273 maternal and 79 cord blood ZDV concentrations were collected. A population pharmacokinetic model was developed to describe ZDV concentrations as a function of time in the mother and the fetus. Fetal exposures resulting from maternal oral administration and infusion were estimated and compared with therapeutic exposures (3–5 mg l−1 h) and to exposure providing higher risk of toxicity (>8.4 mg l−1 h). Different protocols for ZDV administration during labour were simulated. Results The median fetal exposure and the percentage of children with values above 8.4 mg l−1 h were 3.20 mg l−1 h and 0% after maternal oral administration, respectively, and 9.71 mg l−1 h and 51% after maternal infusion during labour. Two options were considered to reduce fetal exposure during labour: (i) maternal infusion rates could be 1 mg kg−1 h−1 during 1 h followed by 0.5 mg kg−1 h−1 and (ii) the mother could only take oral ZDV every 5 h from start of labour until delivery with her neonate having their first ZDV dose as soon as possible after birth. Conclusions Zidovudine exposures are very important during labour and during the first days of a neonate's life. Maternal ZDV dose should be reduced in addition to the neonate doses reduction already proposed.

Pregnant women and their fetuses are exposed to numerous drugs; however, they are orphan populations with respect to the safety and efficacy of drugs. Therefore, the prediction of maternal and fetal drug exposure prior to administration would be highly useful. A physiologically-based pharmacokinetic (PBPK) model for nevirapine, which is metabolized by the cytochrome P450 (CYP) 3A4, 2B6 and 2D6 pathways, was developed to predict maternal and fetal pharmacokinetics (PK). The model was developed in both non-pregnant and pregnant women, and all physiological and enzymatic changes that could impact nevirapine PK were taken into account. Transplacental parameters estimated from ex vivo human placenta perfusion experiments were included in this PBPK model. To validate the model, observed maternal and cord blood concentrations were compared with predicted concentrations, and the impact of fetal clearance on fetal PK was investigated. By implementing physiological changes, including CYP3A4, 2D6 and 2B6 inductions, we predicted a clearance increase of 21 % in late pregnancy. The PBPK model successfully predicted the disposition for both non-pregnant and pregnant populations. Parameters obtained from the ex vivo experiments allowed the prediction of nevirapine concentrations that matched observed cord blood concentrations. The fetal-to-maternal area under the curve ratio (0–24 h interval) was 0.77, and fetal metabolism had no significant effect on fetal PK. The PBPK approach is a useful tool for quantifying a priori the drug exposure of metabolized drugs during pregnancy, and can be applied to evaluate alternative dosing regimens to optimize drug therapy. This approach, including ex vivo human placental perfusion parameters, is a promising approach for predicting human fetal exposure.

We aimed to describe blood plasma (BP) and seminal plasma (SP) pharmacokinetics of emtricitabine (FTC) in HIV-1-infected men, assess its penetration in the male genital tract, and evaluate its impact on seminal plasma HIV load (spVL) detection. Men from the EVARIST ANRS EP49 study receiving combined antiretroviral therapy with FTC and with suppressed BP viral load were included in the study. A total of 236 and 209 FTC BP and SP concentrations, respectively, were available. A population pharmacokinetic model was developed with Monolix 4.1.4. The impact of FTC seminal exposure on spVL detection was explored by receiver operating characteristic (ROC) curves and mixed-effects logistic regressions. FTC BP pharmacokinetics was described by a two-compartment model. The addition of an effect compartment with different input and output constants best described FTC SP pharmacokinetics. No covariates were found to explain the variability in SP. FTC exposures (area under the concentration-time curve from 0 to 24 h [AUC 0–24 ]) were higher in SP than in BP (median AUC 0–24 , 38.04 and 12.95 mg · liter −1 · h, respectively). The median (range) SP-to-BP AUC 0–24 ratio was 2.91 (0.84 to 10.08). Less than 1% of FTC AUC 0–24 ratios were lower than 1. The impact of FTC SP AUC 0–24 or FTC SP-to-BP AUC 0–24 ratio on spVL detection was not significant ( P = 0.943 or 0.893, respectively). This is the first population model describing FTC pharmacokinetics simultaneously in both BP and SP. FTC distributes well in the male genital tract with higher FTC concentrations in SP than in BP. FTC seminal plasma exposures were considered efficient in the majority of men.

The aims of this study were to describe the unbound and total lopinavir (LPV) pharmacokinetics in pregnant women in order to evaluate if a dosing adjustment is necessary during pregnancy. Lopinavir placental transfer is described, and several genetic covariates were tested to explain its variability. A total of 400 maternal, 79 cord blood, and 48 amniotic fluid samples were collected from 208 women for LPV concentration determinations and pharmacokinetics analysis. Among the maternal LPV concentrations, 79 samples were also used to measure the unbound LPV concentrations. Population pharmacokinetics models were developed by using NONMEM software. Two models were developed to describe (i) unbound and total LPV pharmacokinetics and (ii) LPV placental transfer. The pharmacokinetics was best described by a one-compartment model with first-order absorption and elimination. A pregnancy effect was found on maternal clearance (39% increase), whereas the treatment group (monotherapy versus triple therapy) or the genetic polymorphisms did not explain the pharmacokinetics or placental transfer of LPV. Efficient unbound LPV concentrations in nonpregnant women were similar to those measured during the third trimester of pregnancy. Our study showed a 39% increase of maternal total LPV clearance during pregnancy, whereas unbound LPV concentrations were similar to those simulated in nonpregnant women. The genetic polymorphisms selected did not influence the LPV pharmacokinetics or placental transfer. Thus, we suggest that the LPV dosage should not be increased during pregnancy.

The pediatric population is often exposed to drugs without sufficient knowledge about pharmacokinetics. The prediction of accurate clearance values in children, especially in neonates and infants, will improve the rational in dosing decisions. Drug clearances from birth to adulthood were compiled after a systematic review of pharmacokinetic reports. The analysis was performed using NONMEM. Clearance predictions were then evaluated by external validation. Prediction errors were also compared with those obtained from weight-based allometric scaling and physiologically based clearance (PBCL) models. For the analysis, 17 and 15 drugs were used for model building and external validation, respectively. A model based on the adult drug clearance value and taking into account both weight and age was retained. Age-related maturation of clearance reached 90% of the adult value within 1.5 years of life. For children less than 2 years old, allometric scaling alone systematically overestimated clearances. Accounting for age improved the clearance prediction in the 6 months-2 years age group (prediction error < 25%). Predictions obtained from the PBCL approach were close to our results. This analysis established a single equation using the adult clearance value as well as individual age and weight to predict drug clearance in children older than 6 months.

For the first time, a population approach was used to describe abacavir (ABC) pharmacokinetics in HIV-infected pregnant and nonpregnant women. A total of 266 samples from 150 women were obtained. No covariate effect (from age, body weight, pregnancy, or gestational age) on ABC pharmacokinetics was found. Thus, it seems unnecessary to adapt the ABC dosing regimen during pregnancy.

The aims of this study were to describe emtricitabine concentration-time courses in a large population of HIV-1-infected adults, to evaluate the influence of renal function on emtricitabine disposition, and to assess current dosing adjustment recommendations. Emtricitabine blood plasma concentrations were determined from samples collected from 161 adult patients during therapeutic drug monitoring and measured by liquid chromatography coupled to tandem mass spectrometry. The data were analyzed by a population approach. Emtricitabine pharmacokinetics was best described by a two-compartment model in which the absorption and distribution rate constants were assumed to be equal. Typical population parameter estimates (interindividual variability) were apparent elimination and intercompartmental clearances of 15.1 liters/h (17.4%) and 5.75 liters/h, respectively, and apparent central and peripheral volumes of distribution of 42.3 liters and 55.4 liters, respectively. The apparent elimination clearance was significantly related to creatinine clearance (CL CR ), reflecting renal function. For 200 mg once a day (QD), the median area under the concentration-time curve over 24 h (AUC 0-24 ) was 12.5 mg · h/liter for patients with normal renal function (CL CR , >80 ml/min), 14.7 mg · h/liter for patients with mild renal impairment (CL CR , 79 to 50 ml/min), and 17.9 mg · h/liter for patients with moderate renal impairment (CL CR , 49 to 30 ml/min). Simulations of the recommended dosing schemes for the oral solid form of emtricitabine (i.e., 200 mg per 48 h according to renal function) led to lower emtricitabine exposures for patients with moderate renal impairment (median AUC 0-48 , 17.2 mg · h/liter) than for patients with normal renal function (median AUC 0-48 , 25.6 mg · h/liter). Administering 18 ml of emtricitabine oral solution (10 mg/ml) QD to patients with moderate renal impairment should yield emtricitabine exposures similar to those in patients with normal renal function.