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Elagolix, a gonadotropin-releasing hormone receptor antagonist, was recently approved for heavy menstrual bleeding associated with uterine fibroids (UF, Oriahnn) at a dose of 300 mg twice daily (BID) in combination with add-back therapy (oestradiol 1 mg/norethindrone acetate 0.5 mg [E2/NETA] once daily) for 24 months use. The limited duration of treatment is related to elagolix dose- and duration-dependent decrease in oestrogen that is mechanistically linked to changes in bone mineral density (BMD). The work herein supported the extended treatment duration of 24 months.An integrated exposure-response and epidemiological modelling framework of elagolix effects on femoral neck BMD (FN-BMD), informed by real-world data and phase 3 clinical trials data, was developed to predict the time course and magnitude of changes in BMD and its relation to risk of bone fracture in women with UF.Model results indicated that women treated with elagolix 300 mg BID + E2/NETA in the long term (ie,24 months) may experience less than 1% loss in FN-BMD per year, relative to placebo. The exposure-response model simulations and clinical risk factors were used to estimate 10-year risk of fractures using the clinically validated Fracture Risk Assessment Tool (FRAX). The impact of elagolix 300 mg BID + E2/NETA treatment on the 10-year risk of hip or major osteoporotic fractures estimated from the FRAX model was minimal compared to that of placebo.The elagolix integrated exposure-BMD analysis and translation to fracture risk provided an interdisciplinary model-informed drug development framework for clinical benefit-risk evaluation and enabled approval of longer treatment duration to benefit the patient.

BACKGROUND & AIMS: SERENE UC (Study of a Novel Approach to Induction and Maintenance Dosing With Adalimumab in Patients With Moderate to Severe Ulcerative Colitis) evaluated the efficacy of higher adalimumab induction and maintenance dose regimens in patients with ulcerative colitis. METHODS: This phase 3, double-blind, randomized trial included induction and maintenance studies, with a main study (ex-Japan) and Japan substudy. Eligible patients (18-75 years, full Mayo score 6-12, centrally read endoscopy subscore 2-3) were randomized 3:2 to higher induction regimen (adalimumab 160 mg at weeks 0, 1, 2, and 3) or standard induction regimen (160 mg at week 0 and 80 mg at week 2); all received 40 mg at weeks 4 and 6. At week 8, all patients were rerandomized 2:2:1 (main study) to 40 mg every week (ew), 40 mg every other week (eow), or exploratory therapeutic drug monitoring; or 1:1 (Japan substudy) to 40 mg ew or 40 mg eow maintenance regimens. RESULTS: In the main study, 13.3% vs 10.9% of patients receiving the higher induction regimen vs standard induction regimen achieved clinical remission (full Mayo score ≤2 with no subscore >1) at week 8 (induction primary end point; P = .265); among week-8 responders, 39.5% vs 29.0% receiving 40 mg ew vs 40 mg eow achieved clinical remission at week 52 (maintenance primary end point; P = .069). In the integrated (main + Japan) population, 41.1% vs 30.1% of week-8 responders receiving 40 mg ew vs 40 mg eow achieved clinical remission at week 52 (nominal P = .045). Safety profiles were comparable between dosing regimens. CONCLUSION: Although primary end points were not met, a >10% absolute difference in clinical remission was demonstrated with higher adalimumab maintenance dosing. Higher dosing regimens were generally well tolerated and consistent with the known safety profile of adalimumab in ulcerative colitis. CLINICALTRIALS: gov, Number: NCT002209456. ispartof: GASTROENTEROLOGY vol:162 issue:7 pages:1891-1910 ispartof: location:United States status: published

Background Lopinavir/ritonavir (LPV/r-A, Kaletra®), a fixed dose, co-formulated antiviral therapy for the treatment of HIV infection has been used worldwide for over two decades. Both active substances have low solubility in water and low membrane permeability. LPV/r-A tablets contain key excipients critical to ensuring acceptable bioavailability of lopinavir and ritonavir in humans. An established dog pharmacokinetic model demonstrated several generic LPV/r tablet formulations have significant oral bioavailability variability compared to LPV/r-A. Methods Analytical characterizations of LPV/r-B tablets were performed and a clinical study was conducted to assess the relative bioavailability of Kalidavir® (LPV/r-B) 400/100 mg tablets relative to Kaletra® (LPV/r-A) 400/100 mg tablets under fasting conditions. Results The presence of active substances were confirmed in LPV/r-B tablets in an apparent amorphous state at essentially the labeled amounts, and dissolution profiles were generally similar to LPV/r-A tablets. Excipients in the tablet formulation were found to be variable and deviate from the labeled composition. Lopinavir and ritonavir exposures (AUC) following LPV/r-B administration were approximately 90% and 20% lower compared to that of LPV/r-A. Conclusions LPV/r-B was not shown to be bioequivalent to LPV/r-A.

BACKGROUND & AIMS: Dose-optimization strategies for biologic therapies in Crohn's disease (CD) are not well established. The SERENE CD (Study of a Novel Approach to Induction and Maintenance Dosing With Adalimumab in Patients With Moderate to Severe Crohn's Disease) trial evaluated higher vs standard adalimumab induction dosing and clinically adjusted (CA) vs therapeutic drug monitoring (TDM) maintenance strategies in patients with moderately to severely active CD. METHODS: In this phase 3, randomized, double-blind, multicenter trial, eligible adults (Crohn's Disease Activity Index score of 220-450, endoscopic evidence of mucosal inflammation, and previous failure of standard therapies) were randomized to higher induction regimen (adalimumab 160 mg at weeks 0, 1, 2, and 3; n = 308) or standard induction regimen (adalimumab 160 mg at week 0 and 80 mg at week 2; n = 206) followed by 40 mg every other week from week 4 onward. Co-primary end points included clinical remission at week 4 and endoscopic response at week 12. At week 12, patients were re-randomized to maintenance therapy optimized by Crohn's Disease Activity Index and C-reactive protein (CA; n = 92) or serum adalimumab concentrations and/or clinical criteria (TDM; n = 92); exploratory end points were evaluated at week 56. RESULTS: Similar proportions of patients receiving higher induction regimen and standard induction regimen achieved clinical remission at week 4 (44% in both; P = .939) and endoscopic response at week 12 (43% vs 39%, respectively, P = .462). Week 56 efficacy was similar between CA and TDM. Safety profiles were comparable between dosing regimens. CONCLUSIONS: Higher induction regimen was not superior to standard induction regimen, and CA and TDM maintenance strategies were similarly efficacious. Adalimumab therapy was well tolerated, and no new safety concerns were identified. (ClinicalTrials.gov, Number: NCT02065570). ispartof: GASTROENTEROLOGY vol:162 issue:7 pages:1876-1890 ispartof: location:United States status: published

Elagolix is a novel, oral gonadotropin‐releasing hormone receptor antagonist indicated for the management of moderate to severe pain associated with endometriosis and heavy menstrual bleeding associated with uterine fibroids. Consistent with its mechanism of action, elagolix exhibited dose‐dependent suppression of estradiol (E2) in clinical studies. A dose‐response model that describes the relationship between elagolix dosages and average E2 levels was combined with a previously published quantitative systems pharmacology (QSP) model of calcium homeostasis to predict bone mineral density (BMD) changes during and following elagolix treatment. In the QSP model, changes in E2 levels were linked to downstream changes in markers of bone resorption (carboxyterminal cross‐linked telopeptide of type 1 collagen [CTX]), formation (N‐terminal propeptide of type 1 procollagen [P1NP]) and BMD. The BMD, CTX, and P1NP predictions by the QSP model were validated against observed data from four phase III clinical trials of elagolix in premenopausal women with endometriosis. BMD, CTX, and P1NP were successfully described by the QSP model, without any model fitting, suggesting that the model was validated for further predictions of elagolix effects on BMD. Simulations using the validated QSP model demonstrated that elagolix 150 mg once daily dosing for 24 months is predicted to result in −0.91% change from baseline in lumbar spine BMD. The QSP model simulation results were part of the totality of evidence to support the approved duration of therapy for elagolix 150 mg once daily in patients with endometriosis.

Decline of bone mineral density (BMD) during menopause is related to increased risk of fractures in postmenopausal women, however, this relationship in premenopausal women has not been established. To quantify this relationship, real‐world data (RWD) from the National Health and Nutrition Examination Survey (NHANES), and longitudinal data from the elagolix phase III clinical trials were modeled across a wide age range, and covariates were evaluated. The natural changes in femoral neck BMD (FN‐BMD) were well‐described by a bi‐exponential relationship with first‐order BMD formation (k1) and resorption (k2) rate constants. Body mass index (BMI) and race (i.e., Black) were significant predictors indicating that patients with high BMI or Black race experience a relatively lower BMD loss. Simulations suggest that untreated premenopausal women with uterine fibroids (UFs) from elagolix phase III clinical trials (median age 43 years [minimum 25–maximum 53]) lose 0.6% FN‐BMD each year up to menopausal age. For clinical relevance, the epidemiological FRAX model was informed by the simulation results to predict the 10‐year risk of major osteoporotic fracture (MOF). Premenopausal women with UFs, who received placebo only in the elagolix phase III trials, have a projected FN‐BMD of 0.975 g/cm2 at menopause, associated with a 10‐year risk of MOF of 2.3%. Integration of modeling, RWD, and clinical trials data provides a quantitative framework for projecting long‐term postmenopausal risk of fractures, based on natural history of BMD changes in premenopausal women. This framework enables quantitative evaluation of the future risk of MOF for women receiving medical therapies (i.e., GnRH modulators) that adversely affect BMD.

Background and Aims The Phase 3 study ENVISION I demonstrated efficacy and safety of adalimumab in paediatric patients with moderate to severe ulcerative colitis. The protocol-specified high-dose adalimumab regimen was numerically more efficacious than the standard-dose regimen. The objective of this work was to bridge a fixed-dosing regimen to the protocol-specified high-induction/high-maintenance, body weight-based dosing regimen studied in ENVISION I, using a pharmacometrics modelling and simulation approach. Methods A stepwise strategy was implemented, including developing an adalimumab paediatric population pharmacokinetic model; using this model to determine a fixed-dosing regimen in paediatric ulcerative colitis patients which achieves similar concentrations to those observed in ENVISION I patients; determining adalimumab exposure-response relationship using population pharmacokinetic/pharmacodynamic model and data from ENVISION I; simulating clinical remission rate in paediatric ulcerative colitis patients using the Markov exposure-response model and the dosing regimen determined to provide similar efficacy to that observed in ENVISION I. Results Both developed population pharmacokinetic and pharmacokinetic/pharmacodynamic models adequately described the observed data. Adalimumab exposure was identified as a significant predictor of clinical remission at Week 8 based on logistic regression [p Conclusions The population pharmacokinetic/pharmacodynamic model supports the appropriateness of the use of the fixed-dosing regimen in the paediatric ulcerative colitis population.

Elagolix is a novel oral gonadotropin releasing hormone receptor antagonist, that can suppress estradiol in a dose-dependent manner. It is indicated for management of moderate-to-severe pain associated with endometriosis. A population exposure-response model describing the relationship between elagolix exposure and changes in bone mineral density (BMD) was developed using data from four phase III studies in premenopausal women with endometriosis-associated pain. Elagolix pharmacokinetic exposure-dependent changes in BMD were described by an indirect-response maximum effect (Emax ) model through stimulation of bone resorption. African American race, higher body mass index (BMI), and lower type-I collagen C-telopeptide concentrations were significantly associated with higher baseline BMD. Higher BMI was significantly associated with higher bone formation rates. Simulations using the final model demonstrated that elagolix 150 mg q.d. dosing for 24 months is predicted to result in -1.45% (-2.04 to -0.814) decrease from baseline in BMD and were used to support corresponding dosing recommendations in the label.

Elagolix is an oral, non-peptide, gonadotropin-releasing hormone receptor antagonist. It is approved for the treatment of moderate-to-severe pain associated with endometriosis and is being investigated for the treatment of heavy menstrual bleeding associated with uterine fibroids. Use of low-dose hormonal add-back therapy can reduce hypoestrogenic effects associated with elagolix, thus there is a need to determine if there is a pharmacokinetic interaction between elagolix and low-dose hormonal add-back therapy. Two multiple-dose, open-label, single-sequence, non-randomized studies for elagolix 300 mg twice daily with oral (n = 24) and transdermal (n = 36) low-dose add-back therapy (estradiol [E2]/norethindrone acetate [NETA]; 1 mg/0.5 mg oral and 0.51 mg/4.8 mg transdermal) in healthy postmenopausal women were conducted, with pharmacokinetic sampling for E2, estrone (E1), and NETA up to 72 or 96 h after dosing. Pharmacokinetic parameters for hormones were estimated using noncompartmental methods. No change in norethindrone maximum plasma concentration or area under the concentration–time curve was observed when oral E2/NETA was administered with elagolix. For E2, there was a 2-fold increase in maximum plasma concentration and a 1.5-fold increase in the area under the concentration–time curve, and for E1 there was a 1.7-fold increase in maximum plasma concentration when oral E2/NETA was administered with elagolix. Exposures for norethindrone, E2, and E1 were unchanged when transdermal E2/NETA was applied with elagolix administration. Although changes in E2/E1 exposures were observed when oral E2/NETA was co-administered with elagolix, these changes are not considered clinically relevant; and no dose adjustments are recommended when elagolix is co-administered with oral or transdermal low-dose add-back therapy.

Elagolix is an oral gonadotropin‐releasing hormone receptor antagonist indicated for the management of endometriosis‐associated pain and in combination with estradiol/norethindrone acetate indicated for the management of heavy menstrual bleeding associated with uterine leiomyomas (fibroids) in premenopausal women. Elagolix coadministered with estradiol/norethindrone acetate is in late‐stage development for the management of heavy menstrual bleeding associated with uterine fibroids. Based on the in vitro profile of elagolix metabolism and disposition, 9 drug‐drug interaction (DDI) studies evaluating the victim and perpetrator characteristics of elagolix were conducted in 144 healthy volunteers. As a victim of cytochrome P450 (CYPs) and transporter‐mediated DDIs, elagolix area under the curve (AUC) increased by ∼2‐fold following coadministration with ketoconazole and by ∼5‐ and ∼2‐fold with single and multiple doses of rifampin, respectively. As a perpetrator, elagolix decreased midazolam AUC (90% confidence interval) by 54% (50%‐59%) and increased digoxin AUC by 32% (23%‐41%). Elagolix decreased rosuvastatin AUC by 40% (29%‐50%). No clinically significant changes in exposure on coadministration with sertraline or fluconazole occurred. A elagolix 150‐mg once‐daily regimen should be limited to 6 months with strong CYP3A inhibitors and rifampin because of the potential increase in bone mineral density loss, as described in the drug label. A 200‐mg twice‐daily regimen is recommended for no more than 1 month with strong CYP3A inhibitors and not recommended with rifampin. Elagolix is contraindicated with strong organic anion transporter polypeptide B1 inhibitors (eg, cyclosporine and gemfibrozil). Consider increasing the doses of midazolam and rosuvastatin when coadministered with elagolix, and individualize therapy based on patient response. Clinical monitoring is recommended for P‐glycoprotein substrates with a narrow therapeutic window (eg, digoxin). Dose adjustments are not required for sertraline, fluconazole, bupropion (or any CYP2B6 substrate), or elagolix when coadministered.

Elagolix is an orally active, gonadotropin-releasing hormone receptor antagonist approved for the management of endometriosis-associated pain and heavy menstrual bleeding associated with uterine fibroids. Elagolix population pharmacokinetics and factors affecting elagolix exposure in healthy women and women with endometriosis have been reported previously. The purpose of this study was to extend the population pharmacokinetics model with additional modifications to incorporate data from phase III studies of elagolix with hormonal add-back therapy in women with uterine fibroids.Data from 13 clinical studies (a total of 2168 women) consisting of six phase I studies in healthy premenopausal women, four phase III studies in premenopausal women with endometriosis, and three phase III studies in premenopausal women with uterine fibroids were analyzed using a non-linear mixed-effects modeling approach.Elagolix population pharmacokinetics was best described by a two-compartment model with first-order absorption, lag time in absorption, and first-order elimination. Out of the covariates tested on elagolix apparent clearance, apparent volume of distribution, and/or relative bioavailability, only organic anion transporting polypeptide 1B1 genotype status and body weight had a statistically significant but no clinically meaningful effect on elagolix relative bioavailability and apparent volume of distribution, respectively. There were no clinically meaningful differences in elagolix population pharmacokinetics in healthy women or women with endometriosis or uterine fibroids.Elagolix population pharmacokinetics modeling did not reveal any patient-related factors or clinical parameters that would require dose adjustments for the approved dosage of 300 mg twice daily with estradiol 1 mg /norethindrone acetate 0.5 mg daily, in women with heavy menstrual bleeding associated with uterine fibroids.ClinicalTrials.gov identifiers: NCT01620528 (EM-1), NCT01760954 (EM-1-Extend), NCT01931670 (EM-2), NCT02143713 (EM-2-Extend), NCT02654054 (UF-1), NCT02691494 (UF-2), NCT0295494 (UF-Extend).

The clinical pharmacology of elagolix was extensively evaluated in clinical studies in healthy subjects and in women with endometriosis. Elagolix pharmacokinetics (PK) show significant population variability, however they are minimally affected by patients’ baseline characteristics and demographics, except for clinically relevant extrinsic and intrinsic factors such as coadministrated strong organic anion transporting polypeptide (OATP) 1B1 inhibitors and severe hepatic impairment, which are contraindications for the use of elagolix. These studies enabled a comprehensive understanding of elagolix mechanism of action and the downstream pharmacodynamic (PD) effects on gonadotropin and ovarian hormones, as well as full characterization of the PK/PD (PKPD) relationships of elagolix at various dosages, including the approved 150 mg once daily and 200 mg twice daily dosing regimens for the management of moderate to severe pain associated with endometriosis. Several model-based analyses have contributed to understanding of the benefit–risk profile of elagolix in patients with endometriosis, through characterization of the exposure relationship with responder rates, with changes in bone mineral density over time, as well as the interaction with coadministered drugs. Collectively, these studies and analyses served as supportive evidence for the effectiveness of the approved dosages and provided general dosing instructions of the first approved oral gonadotropin-releasing hormone receptor antagonist. Electronic supplementary material The online version of this article (10.1007/s40262-019-00840-7) contains supplementary material, which is available to authorized users.

Biologic treatment options are limited for children with ulcerative colitis. The aim of this study was to assess the safety and efficacy of adalimumab in children with moderate-to-severe ulcerative colitis.The double-blind ENVISION I study was done at 24 hospitals in ten countries. Children (4-17 years) with moderate-to-severe ulcerative colitis despite stable doses of concurrent treatment with oral corticosteroids or immunosuppressants were enrolled. Per the original study design, patients were randomly assigned with an Interactive Voice Response System (IVRS) to receive either high-dose induction adalimumab (2·4 mg/kg [maximum 160 mg] at weeks 0 and 1) or standard-dose induction adalimumab (2·4 mg/kg at week 0 and placebo at week 1); both groups received 1·2 mg/kg (maximum 80 mg) at week 2 and 0·6 mg/kg (maximum 40 mg) at weeks 4 and 6. Patients with partial Mayo score (PMS) response at week 8 (defined as a decrease of two or more points and a decrease of ≥30% from baseline in PMS) were randomly assigned (2:2:1)-using IVRS-to receive either high-dose maintenance adalimumab (0·6 mg/kg weekly), standard-dose maintenance adalimumab (0·6 mg/kg every other week), or placebo up to week 52 (random assignment to the placebo group was ceased mid-trial, as was randomisation in the induction phase with all subsequent patients receiving open-label high-dose induction adalimumab). Coprimary endpoints were the proportion of patients with PMS remission at week 8 (intent-to-treat [ITT]-E population, not including those patients who were not randomised in the induction phase) and full Mayo score (FMS) remission at week 52 in week 8 PMS responders (maintenance ITT-E [mITT-E] population), for which the pooled adalimumab group (patients who received high-dose or standard-dose adalimumab) and the individual dose groups were compared against external adult placebo rates. We report results of the final confirmatory analysis. This trial is registered with ClinicalTrials.gov, NCT02065557.93 children were recruited between Oct 13, 2014, and Sept 5, 2018, to the main study (77 [83%] were randomly assigned [double-blind] to receive high-dose or standard-dose induction adalimumab; 16 [17%] received open-label high-dose induction adalimumab after study design change). At week 8, 74 (80%) children who were PMS responders continued to the maintenance period. 62 (84%) patients were randomly assigned to receive high-dose or standard-dose maintenance adalimumab treatment; 12 (16%) patients received placebo. In patients in the ITT-E population who were randomly assigned to receive high-dose induction adalimumab, a significantly higher proportion of patients were in PMS remission at week 8 (28 [60%] of 47) compared with external placebo (19·8%; p=0·0001). 13 (43%) of 30 patients in the standard-dose induction adalimumab group were in PMS remission at week 8 versus an external placebo rate of 19·8%, but this difference was not significant (p=0·38). Similarly, FMS remission at week 52 in children who were week 8 PMS responders was reported in a significantly higher proportion of patients in mITT-E population who received high-dose maintenance adalimumab (14 [45%] of 31 patients) versus external placebo at week 52 (18·4%; p=0·0001). Nine (29%) of 31 patients in the standard-dose maintenance adalimumab group were in FMS remission at week 52 versus an external placebo rate of 18·4%, but this difference was not significant (p=0·38). Remission rates in the pooled adalimumab groups were significantly better compared with external placebo (PMS remission at week 8: 41 [53%] of 77 patients; p0·0001; FMS remission at week 52: 23 [37%] of 62 patients; p=0·0001). 21 (23%) of 93 patients in the main study had one or more treatment-emergent serious adverse events during any adalimumab exposure. The most common adverse events were headache, anaemia, and ulcerative colitis flare during the induction period and ulcerative colitis flare, headache, and nasopharyngitis during the maintenance period.Clinically meaningful rates of remission and response were reported in children who received adalimumab in this study. No new safety signals were observed, suggesting that adalimumab is an efficacious and safe treatment option for children with moderate-to-severe ulcerative colitis.AbbVie.

Elagolix is an oral gonadotropin-releasing hormone antagonist approved by the US Food and Drug Administration (FDA) for the management of moderate-to-severe pain associated with endometriosis and in combination with estradiol/norethindrone acetate approved for the management of heavy menstrual bleeding associated with uterine leiomyomas (fibroids) in premenopausal women. The objective of this work was to characterize the relationships between elagolix exposures and clinical efficacy response rates for dysmenorrhea (DYS) and nonmenstrual pelvic pain (NMPP) in premenopausal women enrolled in the pivotal phase III studies with moderate-to-severe pain associated with endometriosis. Relationships between elagolix average concentrations (Cavg ) and efficacy responses (DYS and NMPP) were characterized using a nonlinear mixed-effects discrete-time first order Markov modeling approach. Only age was statistically significant for NMPP but not considered clinically relevant. This work indicates that the selection of elagolix dose is not determined based on tested patient demographics, baseline, or endometriosis disease severity measures in covariate analysis. In other words, the work suggests no preference of one regimen over the other to treat endometriosis-associated pain (DYS or NMPP) for any patient subpopulation based on tested covariate groups.

This study aimed to identify the optimal dose of the endothelin-1 receptor antagonist atrasentan with maximal albuminuria reduction and minimal signs of sodium retention, as manifested by increase in bodyweight. Data from the RADAR-JAPAN studies were used, evaluating the effect of 0.75 or 1.25 mg/d of atrasentan in 161 patients with type 2 diabetes and kidney disease. Individual pharmacokinetic parameters were estimated using a population pharmacokinetic approach. Subsequently, changes in the urinary albumin-to-creatinine ratio (UACR) and bodyweight from baseline after 2 weeks' exposure were modelled as a function of the pharmacokinetic parameters. The 0.75 and 1.25 mg doses showed a mean UACR reduction of 34.0% and 40.1%, whereas mean bodyweight increased by 0.9 and 1.1 kg, respectively. A large variation between individuals was observed in the UACR and bodyweight responses. Individual pharmacokinetic parameters correlated significantly with both individual UACR and bodyweight responses (P

Purpose The objective of the current analyses was to characterize the pharmacokinetic properties of atrasentan and the exposure-response relationships for the efficacy end point, urinary albumin to creatinine ratio (UACR), and the treatment-emergent adverse event, peripheral edema, during 8 or 12 weeks of treatment. Methods Results from 3 Phase II, randomized, double-blind, placebo-controlled studies (N = 257) were used for the population pharmacokinetic and exposure-response models. Concentration-time and response data for efficacy and tolerability were analyzed using a nonlinear mixed-effects population analysis and logistic regression approaches. Findings The pharmacokinetic data were adequately described by a 2-compartment model with first-order absorption and elimination. After weight was accounted for, no clinically meaningful differences were found in CL/F or Vd/F of the central compartment between Western and Japanese patients. Exposure-response analyses confirmed the efficacy of atrasentan in reducing UACR, with an estimated decrease in UACR of ≥37% when the atrasentan dose was 0.75 mg or higher. No significant association between atrasentan exposure and the rate of edema was identified at atrasentan doses of 0.5, 0.75, and 1.25 mg. The rates of peripheral edema were comparable in patients receiving active treatment and placebo. Implications The exposure-response relationships for efficacy and tolerability were consistent between Western and Japanese patients. On the basis of these analyses, a dose of 0.75 mg/d was selected for the Phase III trial. ClinicalTrials.gov identifiers: NCT01356849, NCT01399580, and NCT01424319.

Success of treatment withdrawal in patients with non-radiographic axial spondyloarthritis who are in remission remains unknown. The ABILITY-3 study explored the ability to withdraw adalimumab treatment in patients with non-radiographic axial spondyloarthritis who achieved sustained clinical remission after open-label treatment with adalimumab.ABILITY-3 was a multicentre, two-period study done in 107 sites in 20 countries. We enrolled adult patients (≥18 years) diagnosed with non-radiographic axial spondyloarthritis, fulfilling Assessment of SpondyloArthritis international Society classification criteria but not the modified New York radiologic criterion, who had objective evidence of active inflammation, active disease, and inadequate response to at least two non-steroidal anti-inflammatory drugs. Patients who achieved Ankylosing Spondylitis Disease Activity Score (ASDAS) inactive disease (1·3) with open-label adalimumab (40 mg subcutaneously every other week for 28 weeks) at weeks 16, 20, 24, and 28 were randomly assigned (1:1) using an interactive voice or web response system to 40-week, double-blind treatment with adalimumab (continuation) or placebo (withdrawal). The primary efficacy endpoint was the proportion of patients who did not experience a flare (defined as ASDAS ≥2·1 at two consecutive visits) during the double-blind period. Patients who flared were rescued with open-label adalimumab. This study is registered with ClinicalTrials.gov, number NCT01808118.Between June 27, 2013, and October 22, 2015, 673 patients were enrolled to the study. The trial completed on April 14, 2017. Of 673 enrolled patients, 305 (45%) achieved sustained remission and were randomly assigned to double-blind treatment (152 patients to adalimumab and 153 to placebo). A greater proportion of patients continuing adalimumab than those receiving placebo did not experience a flare (107 [70%] of 152 patients vs 72 [47%] of 153 patients; p0·0001) up to and including week 68. Among 673 patients receiving adalimumab at any time, 516 (77%) patients reported an adverse event and 28 (4%) experienced a serious adverse event. The most common adverse events in both the adalimumab and placebo groups were nasopharyngitis (25 [16%] vs 20 [13%]), upper respiratory tract infection (20 [13%] vs 12 [8%]), and worsening of axial spondyloarthritis (ten [7%] vs 21 [14%]).In patients with active non-radiographic axial spondyloarthritis who achieved sustained remission with adalimumab, continued therapy was associated with significantly fewer patients flaring than was treatment withdrawal.AbbVie.

Hidradenitis suppurativa (HS) is a serious, debilitating, chronic inflammatory skin disease. Adalimumab is a fully human, immunoglobulin G1 monoclonal antibody specific for tumor necrosis factor-alpha recently approved for use in patients with HS. The aim of this study is to describe the population pharmacokinetics and immunogenicity of adalimumab in adult patients with HS. Data from one phase II and two phase III studies were included in the analysis. Serial serum adalimumab concentrations and anti-adalimumab antibody (AAA) development status were used to develop the population pharmacokinetic model. The population pharmacokinetic analysis involved evaluating the effects of potential covariates on adalimumab pharmacokinetics. Mean serum adalimumab concentrations after 40-mg weekly dosing reached steady state (10–12 µg/mL in the phase II study and 7 µg/mL in the phase III studies) by week 2 and were maintained through week 12. The percentage of patients testing positive for AAA was low (10% in the phase II study and 7% in the phase III studies). Adalimumab pharmacokinetics was described by a one-compartment model with first-order absorption. Significant covariates for clearance included the presence of AAA, baseline C-reactive protein, and baseline body weight. Adalimumab pharmacokinetics in HS patients was described using a one-compartment model with weight, baseline C-reactive protein, and AAA affecting adalimumab exposure. AAA development results in decreased adalimumab concentrations with a potential decrease in efficacy. Serum adalimumab concentrations in HS patients receiving 40-mg weekly dosing were similar to those observed in other indications under approved dosing regimens.

Background: Dose escalation is often recommended for loss of response in anti-TNFα-treated patients with Crohn’s disease (CD). This 52-week phase 3, multicenter study investigated the efficacy and safety of escalation to adalimumab 80 mg every other week (EOW) in Japanese patients with CD who lost response to maintenance adalimumab 40 mg EOW. Methods: Twenty-eight patients aged ≥15 years with moderately to severely active CD who had previously attained and subsequently lost clinical response to maintenance ada limumab received open-label adalimumab 80 mg EOW during weeks 0–50. Loss of response was defined as CD activity index (CDAI) ≥200, increases in CDAI ≥50 from minimum observed value, and C-reactive protein (CRP) ≥1 mg/dL at screening. The primary endpoint was the proportion of patients achieving a CDAI decrease ≥50 (CR-50) from baseline at week 8. Results: At weeks 8 and 52, 75.0 and 57.1% of patients achieved CR-50 and 25.0 and 35.7% achieved clinical remission (CDAI < 150), respectively; median CRP changes from baseline were −0.39 and −0.77 mg/dL, respectively. Most treatment-emergent adverse events were mild to moderate. Conclusions: Adalimumab dose escalation to 80 mg EOW improved CD activity in patients who had lost response to maintenance adalimumab, with no new safety signals. (ClinicalTrials.gov Identifier: NCT01958827.)

Summary Background Adalimumab is approved for use in patients with moderate to severe Crohn's disease (CD) or ulcerative colitis (UC) who have not achieved disease control with conventional therapies including corticosteroids and/or immunomodulators (IMM). Aim To analyse six studies that examined efficacy, pharmacokinetics and safety of combination IMM/adalimumab therapy, compared with adalimumab monotherapy in patients with inadequate disease control on conventional therapy. Methods Patients with moderate to severe CD or UC from randomised, double‐blind, placebo‐controlled trials were analysed. Adalimumab was added to background therapy; patients were categorised as receiving adalimumab monotherapy (CD induction, n = 245, maintenance, n = 185; UC induction, n = 213, maintenance, n = 157) or combination therapy (CD induction, n = 139, maintenance, n = 139; UC induction, n = 140, maintenance, n = 100) according to baseline immunomodulator use. Efficacy was reported for the intent‐to‐treat populations from each study, with remission defined as CD activity index 1 for UC. Safety was assessed via adverse events. Results The proportions of patients achieving remission were similar for adalimumab monotherapy and immunomodulator combination therapy in all studies. Median adalimumab concentrations at week 4 or 8 were numerically but not significantly higher with adalimumab combination therapy vs. monotherapy in the CD and UC studies respectively. Incidence and rate of adverse events was similar for adalimumab monotherapy and combination therapy. Conclusions Post hoc analysis of six randomised, controlled trials demonstrated no efficacy benefits with immunomodulator/adalimumab combination therapy, compared with adalimumab monotherapy in CD and UC patients with inadequate disease control on conventional therapy; the safety of the two treatment approaches was comparable.

Supplemental Digital Content is Available in the Text. Article first published online 7 March 2016., Background: The efficacy of adalimumab in inducing and maintaining remission in children with moderately to severely active Crohn's disease was shown in the IMAgINE 1 trial (NCT00409682). As per protocol, nonresponders or patients experiencing flare(s) on every other week (EOW) maintenance dosing could escalate to weekly dosing; we aimed to determine the therapeutic benefits of weekly dose escalation in this subpopulation. Methods: Week 52 remission and response rates were assessed in patients who escalated to weekly dosing from their previous EOW schedule, which was according to randomized treatment dose (higher dose [HD] adalimumab [≥40 kg, 40 mg EOW

Hidradenitis suppurativa is a painful, chronic inflammatory skin disease with few options for effective treatment. In a phase 2 trial, adalimumab, an antibody against tumor necrosis factor α, showed efficacy against hidradenitis suppurativa.PIONEER I and II were similarly designed, phase 3 multicenter trials of adalimumab for hidradenitis suppurativa, with two double-blind, placebo-controlled periods. In period 1, patients were randomly assigned in a 1:1 ratio to 40 mg of adalimumab weekly or matching placebo for 12 weeks. In period 2, patients were reassigned to adalimumab at a weekly or every-other-week dose or to placebo for 24 weeks. The primary end point was a clinical response, defined as at least a 50% reduction from baseline in the abscess and inflammatory-nodule count, with no increase in abscess or draining-fistula counts, at week 12.We enrolled 307 patients in PIONEER I and 326 in PIONEER II. Clinical response rates at week 12 were significantly higher for the groups receiving adalimumab weekly than for the placebo groups: 41.8% versus 26.0% in PIONEER I (P=0.003) and 58.9% versus 27.6% in PIONEER II (P0.001). Patients receiving adalimumab had significantly greater improvement than the placebo groups in rank-ordered secondary outcomes (lesions, pain, and the modified Sartorius score for disease severity) at week 12 in PIONEER II only. Serious adverse events in period 1 (excluding worsening of underlying disease) occurred in 1.3% of patients receiving adalimumab and 1.3% of those receiving placebo in PIONEER I and in 1.8% and 3.7% of patients, respectively, in PIONEER II. In period 2, the rates of serious adverse events were 4.6% or less in all the groups in both studies, with no significant between-group differences.Treatment with adalimumab (40 mg weekly), as compared with placebo, resulted in significantly higher clinical response rates in both trials at 12 weeks; rates of serious adverse events were similar in the study groups. (Funded by AbbVie; ClinicalTrials.gov numbers, NCT01468207 and NCT01468233 for PIONEER I and PIONEER II, respectively.).

Hidradenitis suppurativa is a chronic skin disease with a significant genetic component and prevalence from 0.5% to 4%. Adalimumab is the only treatment approved by either the European Medicines Agency or the U.S. Food and Drug Administration for the management of moderate to severe hidradenitis suppurativa. To identify genetic variants associated with adalimumab response, we performed a genome-wide association study (GWAS) from the most extensive two phase 3 hidradenitis suppurativa clinical trials (PIONEER I and II) to date. Through direct genotyping and imputation, we tested almost 7 million genetic variants with minor allele frequency > 5% and identified one single linkage disequilibrium block, located in the intron of the BCL2 gene, which reached genome-wide significance (lead single-nucleotide polymorphism, rs59532114; P = 2.35E–08). Bioinformatic analysis and functional genomics experiments suggested a correlation of the most strongly associated single-nucleotide polymorphism minor allele with increased BCL2 gene and protein expressions in hair follicle tissues. In reciprocal knockdown experiments, we found that BCL2 is down-regulated by TNF inhibition. These results highlight a pathway that involves BCL2 in response to adalimumab. Further work is required to determine how this pathway influences adalimumab effectiveness in patients with hidradenitis suppurativa.

Background Low trough levels of the tumour necrosis factor inhibitor, adalimumab (ADL), and anti-ADL antibodies (AAA) were reported to be correlated with lack of response at later time points in patients (pts) with rheumatoid arthritis (RA).1 Objectives To assess the ability of ADL trough levels and clinical assessments at Week 12 to predict clinical remission (REM) after 24 weeks (wks) of treatment with ADL ±methotrexate (MTX) in established RA pts. Methods Data from MTX inadequate responders (MTX-IR) pts with established RA with available measurement of ADL trough levels and clinical assessments at Wks 12 and 24 from several clinical trials were pooled: for pts who received ADL+MTX combination therapy from DE009, DE019, M10–261 and M13–390; for pts who received ADL monotherapy from DE011, M10–261 and M13–390. Efficacy endpoints at Wk 24 were DAS28-CRP Results Based on the cutoffs selected by the predictive model, ADL concentrations at Wk 12 were only slightly predictive for Wk 24 clinical assessment in the ADL monotherapy group, but not in the ADL+MTX group (table 1). However, based on achievement of the specified CDAI, SDAI or DAS28-CRP score at Wk 12 (selected by the model), pts were correctly predicted to reach Wk 24 REM or LDA with an accuracy of 80%–90% and area under the receiver operating characteristic curve (AUC) of 75%–90% (table 2). As an example, pts on ADL monotherapy with DAS28 Conclusions The ADL concentrations at Week 12 selected by the prediction model were weak predictors of disease control at 6 months, especially for pts on ADL+MTX combination therapy. However, using the model-selected cutoffs of composite clinical endpoints at Wk 12, disease control after 6 months of ADL±MTX treatment could be correctly predicted in 70%–80% of pts. References [1] Jani, et al. Arthritis & Rheumatol2015. [2] Huang X, et al. Statistics in Medicine2017. Acknowledgements AbbVie Inc was the study sponsor, contributed to study design, data collection, analysis and interpretation, and to writing, reviewing, and approval of final version. Medical writing support was provided by Naina Barretto, PhD, of AbbVie, Inc. Disclosure of Interest J. Smolen Grant/research support from: AbbVie Inc, Consultant for: AbbVie Inc, N. Mostafa Shareholder of: AbbVie Inc, Employee of: AbbVie Inc, X. Huang Shareholder of: AbbVie Inc, Employee of: AbbVie Inc, P. Noertersheuser Shareholder of: AbbVie Inc, Employee of: AbbVie Inc, B. Kluender Shareholder of: AbbVie Inc, Employee of: AbbVie Inc, K. Chen Shareholder of: AbbVie Inc, Employee of: AbbVie Inc, J. Kalabic Shareholder of: AbbVie Inc, Employee of: AbbVie Inc, I. Sainsbury Shareholder of: AbbVie Inc, Employee of: AbbVie Inc, R. Oerlemans Shareholder of: AbbVie Inc, Employee of: AbbVie Inc, S. Florentinus Shareholder of: AbbVie Inc, Employee of: AbbVie Inc, G. Burmester Grant/research support from: AbbVie Inc., Bristol-Myers Squibb, Merck, Roche, Pfizer, and UCB, Consultant for: AbbVie Inc., Bristol-Myers Squibb, Merck, Roche, Pfizer, and UCB, Speakers bureau: AbbVie Inc., Bristol-Myers Squibb, Merck, Roche, Pfizer, and UCB

Background In patients (pts) with active non-radiographic axial spondyloarthritis (nr-axSpA) in the ABILITY-3 study who achieved sustained remission with adalimumab (ADA), continued ADA therapy was associated with significantly fewer pts flaring than treatment withdrawal. Sustained remission is an important treatment goal in pts with nr-axSpA, but factors predicting sustained remission and absence of flare are unknown. Objectives To determine whether an ADA concentration threshold is predictive of achievement of sustained remission and absence of flare in pts with nr-axSpA. Methods ABILITY-3 included a 28-wk open-label (OL) ADA (40 mg every other wk) lead-in in which pts who achieved sustained remission (ASDAS Results Of 673 pts enrolled in the OL phase, 305 met criteria for remission at wk 28 and were randomised to DB treatment. Mean ±SD ADA trough concentrations were 6.68±5.23 µg/mL at wk 12 and 8.36±5.27 µg/mL at wk 28. During the DB phase, 81 and 45 pts flared and 68 and 36 pts received ≥12 wks of OL ADA rescue in PBO (n=153) and ADA (n=152) arms, respectively. ADA mean ±SD trough concentration at wk 68 for pts randomised to DB ADA with flare (7.64±5.22 µg/mL) was slightly lower than for DB ADA pts without flare (8.12±4.35 µg/mL). ROC curves showed AUC values≤0.6 for achieving sustained remission by wk 28 and absence of flare at wk 68, with no concentration threshold meeting sensitivity and specificity criteria for reliable prediction of such endpoints (figure 1). Conclusions ROC analyses did not identify an ADA trough concentration threshold that reliably predicted whether a pt with nr-axSpA would achieve sustained remission (by wk 28) or absence of flare (at wk 68). Acknowledgements AbbVie funded the study and approved the abstract for submission. Medical writing support was provided by Janet Matsuura, PhD, of Complete Publication Solutions, LLC (North Wales, PA) and was funded by AbbVie. Disclosure of Interest N. Kwatra Employee of: AbbVie, M. Magrey Grant/research support from: Amgen, AbbVie, and UCB Pharma, Consultant for: UCB and Janssen, P. Mease Grant/research support from: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Janssen, Lilly, Novartis, Pfizer, Sun Pharma, and UCB, Consultant for: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Janssen, Lilly, Novartis, Pfizer, Sun Pharma, and UCB, Speakers bureau: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Genentech, Janssen, Novartis, Pfizer, and UCB, J. Sieper Consultant for: AbbVie, Janssen, Lilly, Merck, Novartis, Pfizer, Sun Pharma, and UCB, Speakers bureau: AbbVie, Janssen, Lilly, Merck, Novartis, Pfizer, and UCB, R. Landewe Grant/research support from: Abbott, Amgen, Centocor, Novartis, Pfizer, Roche, Schering-Plough, UCB, and Wyeth, Consultant for: Abbott/AbbVie, Ablynx, Amgen, Astra-Zeneca, Bristol Myers Squibb, Celgene, Janssen (formerly Centocor), Galapagos, GlaxoSmithKline, Novartis, Novo-Nordisk, Merck, Pfizer, Roche, Schering-Plough, TiGenix, UCB, and Wyeth, Speakers bureau: Abbott/AbbVie, Amgen, Bristol Myers Squibb, Janssen (formerly Centocor), Merck, Pfizer, Roche, Schering-Plough, UCB, and Wyeth, X. Wang Employee of: AbbVie, A. Lertratanakul Employee of: AbbVie, J. Anderson Employee of: AbbVie, N. Mostafa Employee of: AbbVie

Background In the IMAgINE 1 study, adalimumab induced and maintained remission of moderate-to-severe Crohn's disease in children. Aim To assess the efficacy, pharmacokinetics, immunogenicity and safety of immunomodulator and adalimumab combination therapy vs adalimumab monotherapy in paediatric patients with Crohn's disease. Methods Patients 6-17 years old with moderate-to-severe Crohn's disease (n = 192) received weight-based adalimumab induction at baseline and week 2. At week 4, 188 patients were randomised to high-dose or low-dose adalimumab. Patients receiving immunomodulators (investigator's decision) at baseline maintained a stable dose until week 26; patients could then discontinue immunomodulators. Adalimumab serum concentrations were measured at weeks 4, 26 and 52. Safety was evaluated at each study visit. Data were analysed using non-responder imputation (NRI; week 4) or modified NRI (weeks 26; 52). Results At week 4, patients with (n = 117) and without (n = 71) baseline immunomodulator use had similar response (79%; 87%; P = 0.235) and remission (26%; 30%; P = 0.737) rates. At week 26, patients with and without baseline immunomodulators had no significant difference in response (68%; 55%; P = 0.086) or remission (41%; 30%; P = 0.122). At week 52, patients with (n = 82) and without (n = 106) immunomodulator use had no significant difference in response (56%; 46%; P = 0.189) or remission (38%; 33%; P = 0.539). Adalimumab serum trough concentrations and serious infection rates (7%; 6%) were not significantly different between groups. Conclusions Analyses found no statistically significant difference in response or remission between patients receiving adalimumab monotherapy vs immunomodulator and adalimumab combination therapy. Serious and infectious adverse event rates were similar between groups.

Elagolix is a novel, orally active, non-peptide, competitive gonadotropin-releasing hormone (GnRH) receptor antagonist in development for the management of endometriosis with associated pain and heavy menstrual bleeding due to uterine fibroids. The pharmacokinetics of elagolix have been well-characterized in phase I studies; however, elagolix population pharmacokinetics have not been previously reported. Therefore, a robust model was developed to describe elagolix population pharmacokinetics and to evaluate factors affecting elagolix pharmacokinetic parameters. The data from nine clinical studies (a total of 1624 women) were included in the analysis: five phase I studies in healthy, premenopausal women and four phase III studies in premenopausal women with endometriosis. Elagolix population pharmacokinetics were best described by a two-compartment model with a lag time in absorption. Of the 15 covariates tested for effect on elagolix apparent clearance (CL/F) and/or volume of distribution only one covariate, organic anion transporting polypeptide (OATP) 1B1 genotype status, had a statistically significant, but not clinically meaningful, effect on elagolix CL/F. Elagolix pharmacokinetics were not affected by patient demographics and were similar between healthy women and women with endometriosis. Clinical Trial Registration Numbers NCT01403038, NCT01620528, NCT01760954, NCT01931670, NCT02143713.

Background Veliparib (ABT-888) is a potent, orally bioavailable, small-molecule inhibitor of the DNA repair enzymes poly ADP-ribose polymerase-1 and -2. Veliparib enhances the efficacy of temozolomide (TMZ) and other cytotoxic agents in preclinical tumor models. Patients and methods In this multicenter, double-blind trial, adults with unresectable stage III or IV metastatic melanoma were randomized 1:1:1 to TMZ plus veliparib 20 or 40 mg, or placebo twice daily. Efficacy end points included progression-free survival (PFS), overall survival (OS), and objective response rate (ORR). Results Patients (N = 346) were randomized between February 2009 and January 2010. Median [95% confidence interval (CI)] PFS was 3.7 (3.0–5.5), 3.6 (1.9–4.1), and 2 (1.9–3.7) months in the 20-mg, 40-mg, and placebo arms, respectively. Median (95% CI) OS was 10.8 (9.0–13.1), 13.6 (11.4–15.9), and 12.9 (9.8–14.3) months, respectively; ORR was 10.3%, 8.7%, and 7.0%. Exploratory analyses showed patients with low ERCC1 expression had longer PFS when TMZ was combined with veliparib. Toxicities were as expected for TMZ. The frequencies of thrombocytopenia, neutropenia, and leukopenia were significantly increased in the veliparib groups. Grade 3 or 4 adverse events, mainly hematologic toxicities, were seen in 55%, 63%, and 41% of patients in the 20-mg, 40-mg, and placebo arms, respectively. Conclusions Median PFS with 20 and 40 mg veliparib almost doubled numerically compared with placebo, but the improvements did not reach statistical significance. OS was not increased with veliparib. Toxicities were similar to TMZ monotherapy, but with increased frequency.

Veliparib, a potent, oral PARP inhibitor, potentiates the antitumor activity of radiation therapy and crosses the blood-brain barrier. This was a phase 1 dose-escalation study evaluating the safety, and secondarily the antitumor activity of veliparib in combination with whole brain radiation therapy (WBRT) in patients with brain metastases, in order to power future trials. Patients with brain metastases from primary solid tumors were treated with WBRT (30.0 or 37.5 Gy in 10 or 15 fractions) and veliparib (escalating doses of 10-300 mg, orally BID). Safety and tumor response were assessed. Observed survival was compared to predicted survival based on a published nomogram. Eighty-one patients (median age 58 years) were treated. The most common primary tumor types were non-small cell lung (NSCLC; n = 34) and breast cancer (n = 25). The most common AEs deemed possibly related to veliparib (AEs, ≥15 %) were fatigue (30 %), nausea (22 %), and decreased appetite (15 %). Fatigue (5 %), hypokalemia and hyponatremia (3 % each) were the only Grade 3/4 AEs deemed possibly related to veliparib observed in ≥2 patients. Although this was an uncontrolled study, preliminary efficacy results were better than predicted: the median survival time (MST, 95 % CI) for the NSCLC subgroup was 10.0 mo (3.9-13.5) and for the breast cancer subgroup was 7.7 mo (2.8-15.0) compared to a nomogram-model-predicted MST of 3.5 mo (3.3-3.8) and 4.9 mo (4.2-5.5). The addition of veliparib to WBRT did not identify new toxicities when compared to WBRT alone. Based on encouraging safety and preliminary efficacy results, a randomized, controlled phase 2b study is ongoing.

The pharmacokinetics (PK) and pharmacodynamics of two leuprolide acetate (LA) 45 mg 6-month depot formulations were characterized in prostate cancer patients. Subjects (planned N = 150 in each cohort) received two intramuscular injections of LA Formulation-A or Formulation-B administered 24 weeks apart. Samples were collected for the measurement of testosterone, LH (all subjects) and leuprolide (in a subset of subjects approximately N = 24 in each cohort) at the same time points. Leuprolide PK profile showed an initial peak followed by a rapid decline over the first week post-dose, with mean leuprolide concentrations staying relatively constant through the end of 24-week period. Mean testosterone and LH serum concentrations showed initial increases above baseline values after the first dose and then decreased to 16.0 ng/dL and 0.6 mIU/mL by Week 4 for Formulation-A and were maintained at ≤14.3 ng/dL and 0.4 mIU/mL, thereafter, with negligible mean increases after the second dose. Formulation-A showed a lower initial peak and higher leuprolide concentration during the sustained release phase which may explain higher testosterone suppression rates for Formulation-A compared to Formulation-B. Differences in PK between LA depot formulations were reflected in pharmacodynamic responses, with a higher rate of testosterone suppression and less escapes and acute-on-chronic responses for Formulation-A.

A pharmacokinetic substudy was conducted within a phase 3 clinical trial that evaluated the efficacy and safety of two leuprolide acetate 3-month depot formulations in children with central precocious puberty (CPP), where the pharmacokinetics of leuprolide and the exposure–response relationship between leuprolide concentration and the probability of luteinizing hormone (LH) suppression were assessed. Children diagnosed with CPP (N = 42 in each dosing cohort), who were treatment naive or previously treated, received a total of two intramuscular injections of either leuprolide acetate depot 11.25 or 30 mg formulations administered 3 months apart. Serial blood samples were collected for leuprolide concentration determination in a subset of subjects (N = 24 in each cohort). One-way analysis of covariance was used to assess dose proportionality. The probability of LH suppression (peak-stimulated LH concentrations

Background Adalimumab is a tumour necrosis factor-alpha antibody approved for treatment of moderate to severe chronic plaque psoriasis. Objective To characterise population pharmacokinetics of adalimumab 40 mg every other week dosing regimen and impact of immunogenicity on pharmacokinetics, efficacy and safety in psoriasis patients. Methods Patients were enrolled in a Phase 3 study comprising a 16-week double-blind, placebo-controlled period, a 17-week open-label period for Week 16 Psoriasis Area and Severity Index (PASI) 75 responders, and a 19-week double-blind, placebo-controlled period for Week 33 PASI 75 responders. Serum adalimumab and anti-adalimumab antibody (AAA) concentrations were measured and a population pharmacokinetic model devleoped to identify patient/disease factors affecting adalimumab pharmacokinetics. Impact of immunogenicity on treatment efficacy and safety was also assessed. Results Week 33 mean adalimumab concentration was 5.2 μg/mL. Week 16 responders had higher adalimumab concentrations than non-responders (6.3 vs. 2.2 μg/mL). Bodyweight and study were significant covariates in population pharmacokinetic model with weight accounting for 19% and 29% of variability in adalimumab clearance and volume of distribution, respectively. A total of 8.8% of adalimumab-treated patients tested AAA positive and had twofold higher adalimumab clearance. PASI 75 response rate was comparable between AAA+ and AAA− patients at Weeks 33 and 52 (Week 33: 36% vs. 22.5%, Week 52: 21.1% vs. 17.8%) and adverse events incidence was similar between the two groups. Conclusions Patient weight and study significantly affect adalimumab clearance and volume of distribution in psoriasis patients. Development of AAAs result in lower adalimumab exposure and efficacy with no effect on adverse events incidence.

A phase 1 study was conducted to evaluate the bioavailability and food effect of a new veliparib formulation in subjects with solid tumors.Subjects (planned: Stage I, N = 20; Stage II, N = 16) received four regimens of a single oral dose of veliparib utilizing a group-sequential design. Subjects were administered single doses of 40 mg veliparib supplied as four 10 mg current formulation, four 10 mg new formulation and one 40 mg new formulation under fasting conditions and under non-fasting conditions. Serial blood samples were collected for the determination of veliparib pharmacokinetics. At the end of Stage I, the relative bioavailability between each pair of regimens was assessed by a two one-sided tests procedure from the analyses of the natural logarithms of C(max) and AUC. A 92.7 % confidence interval within the 0.80-1.25 range between each regimen pair determined bioequivalence.Four 10 mg current formulation capsules, four 10 mg new formulation and one 40 mg new formulation were bioequivalent with respect to C(max) and AUC under fasting conditions. The administration of a high-fat meal did not have a significant effect on AUC and only caused a slight decrease in veliparib C(max) (17 %) and a delay of approximately 1 h in T(max).The 40 mg new capsule was bioequivalent to currently used formulation. Food had no effect on the extent of veliparib absorption and only a small (17 %) decrease in peak exposure of veliparib.

Veliparib (ABT-888) is a potent oral inhibitor of Poly(ADP-ribose) polymerase enzyme that is currently in development for the treatment of non-hematologic and hematologic malignancies. This analysis characterizes the population pharmacokinetics of veliparib, including developing a structural pharmacokinetic model and testing patient demographics and covariates for potential influence on veliparib pharmacokinetics in patients with non-hematologic malignancies.The analysis dataset included 3,542 veliparib concentration values from 325 patients with non-hematologic malignancies enrolled in three phase I and one phase II studies. Population pharmacokinetic modeling was performed using NONMEM. The likelihood ratio test was used for comparison of nested models, and visual predictive check was employed for model qualification. Covariates tested included body size measures, creatinine clearance (CLCR), formulation, age, sex, race, liver function tests, and coadministration with temozolomide.A one-compartment model with first-order absorption and elimination adequately described veliparib pharmacokinetics. The final model included fixed effects for CLCR on veliparib oral clearance (CL/F) and lean body mass (LBM) on volume of distribution (V d/F). CL/F and V d/F were 20.9 L/h (for a CLCR of 100 mL/min) and 173 L (for an LBM of 56 kg), respectively.Only LBM and CLCR were found to be determinants of veliparib V d/F and CL/F, respectively. Dosage adjustments of veliparib on the basis of body size, age, sex, race, liver function, and temozolomide coadministration are not necessary in patients with non-hematologic malignancies. This is the first study to characterize the population pharmacokinetics of veliparib, and the developed model will be used to conduct simulations and evaluate veliparib exposure-response relationships.

The pharmacokinetics (PK) and pharmacodynamics of two leuprolide acetate (LA) 45 mg 6-month depot formulations were characterized in prostate cancer patients. Subjects (planned N = 150 in each cohort) received two intramuscular injections of LA Formulation-A or Formulation-B administered 24 weeks apart. Samples were collected for the measurement of testosterone, LH (all subjects) and leuprolide (in a subset of subjects approximately N = 24 in each cohort) at the same time points. Leuprolide PK profile showed an initial peak followed by a rapid decline over the first week post-dose, with mean leuprolide concentrations staying relatively constant through the end of 24-week period. Mean testosterone and LH serum concentrations showed initial increases above baseline values after the first dose and then decreased to 16.0 ng/dL and 0.6 mIU/mL by Week 4 for Formulation-A and were maintained at ≤14.3 ng/dL and 0.4 mIU/mL, thereafter, with negligible mean increases after the second dose. Formulation-A showed a lower initial peak and higher leuprolide concentration during the sustained release phase which may explain higher testosterone suppression rates for Formulation-A compared to Formulation-B. Differences in PK between LA depot formulations were reflected in pharmacodynamic responses, with a higher rate of testosterone suppression and less escapes and acute-on-chronic responses for Formulation-A.

Background/Aims This was a Phase 2 study (NCT02015793) to evaluate the pharmacokinetics, safety, and efficacy of adalimumab in Chinese patients with Crohn's disease (CD). Methods Thirty, adult Chinese patients with CD (CD Activity Index [CDAI] 220–450; high-sensitivity [hs]-C-reactive protein [CRP] ≥3 mg/L) received double-blind adalimumab 160/80 mg or 80/40 mg at weeks 0/2, followed by 40 mg at weeks 4 and 6. An open-label extension period occurred from weeks 8–26; patients received 40 mg adalimumab every other week. Serum adalimumab concentration and change from baseline in fecal calprotectin (FC) were measured during the double-blind period. Clinical remission (CDAI