Venetoclax in biomarker-selected multiple myeloma patients: Impact of exposure on clinical efficacy and safety.

Venetoclax, a potent BCL-2 inhibitor, is currently under development for treatment of t(11;14) Multiple myeloma (MM). The objective of this research was to investigate the exposure-response relationships of venetoclax for a phase 1/2 study evaluating venetoclax monotherapy or in combination with dexamethasone in relapsed or refractory MM. A total of 117 patients receiving venetoclax at 300, 600, 800, 900, or 1200 mg were included in the analysis. The impact of venetoclax exposures on efficacy (objective response rate [ORR], progression-free survival [PFS] and overall survival [OS]) as well as safety (treatment-emergent adverse effects (grade ≥3) of neutropenia, infection, and any grade of serious treatment-emergent adverse effects) was evaluated. In the t(11;14)-positive subpopulation, venetoclax exposure relationships to PFS and OS indicated a trend of longer PFS and OS with higher exposures. Moreover, logistic regression analyses for clinical response (ORR and ≥VGPR rate) demonstrated a statistically significant (p < 0.05) relationship with exposure. Evaluation of the exposure-safety relationships demonstrated a lack of a relationship between venetoclax exposures (AUCavg ) and grade ≥3 infections, grade ≥3 neutropenia, grade ≥3 treatment-emergent adverse events or any grade serious treatment-emergent adverse events. These findings support further study of venetoclax at 800 mg QD dose in combination with dexamethasone in the t(11;14)-positive patient population where increased efficacy was observed without an increase in safety events.Clinical Trial: NCT01794520 registered 20 February 2013.

Population pharmacokinetic and exposure-response modelling to inform upadacitinib dose selection in adolescent and adult patients with atopic dermatitis.

AIMS: First, population pharmacokinetic analyses were used to characterize upadacitinib pharmacokinetics in adolescent and adult participants with atopic dermatitis (AD) and to identify patient covariates that may impact upadacitinib pharmacokinetics. Second, the exposure-response relationship for upadacitinib with efficacy and safety endpoints, and the effect of age and concomitant use of topical corticosteroids (TCS) on the exposure-response relationship and dose selection for patients with AD were evaluated. METHODS: A two-compartment model with combined first- and zero-order absorption adequately characterized the upadacitinib concentration-time profiles in 911 healthy volunteer adolescent and adult participants with AD who received upadacitinib 15 or 30 mg orally once daily (QD) as monotherapy or in combination with TCS for 16 weeks. Logistic regression models were developed to characterize the exposure-efficacy and safety relationships, and simulations were performed based on final exposure-response models to predict efficacy responses in participants with AD who received placebo or upadacitinib as monotherapy or in combination with TCS. RESULTS: Upadacitinib exposures were comparable between adolescents and adults. Mild or moderate renal impairment was predicted to increase the upadacitinib area under the plasma concentration-time curve from time zero to 24 h after dosing (AUC24 ) approximately 12% and 25%, respectively, compared to participants with normal renal function. Female participants were predicted to have 20% higher AUC24 compared to male participants. Participants with AD were predicted to have 18% higher AUC24 compared to healthy participants. Simulated clinical efficacy responses showed added clinical efficacy benefit for all endpoints evaluated (8-14%) with the upadacitinib 30 mg once-daily regimen compared to 15 mg once-daily in both age groups. In participants receiving upadacitinib in combination with TCS, significant exposure-dependent increases in upadacitinib efficacy endpoints were observed. No significant effects of age or weight were identified in any of the exposure-response models. CONCLUSION: The results of these analyses support the dose justification for upadacitinib in adult and adolescent patients with moderate to severe AD.

Venetoclax exposure-efficacy and exposure-safety relationships in patients with treatment-naïve acute myeloid leukemia who are ineligible for intensive chemotherapy.

This study evaluated venetoclax population pharmacokinetics (popPK) in patients with treatment-naïve acute myeloid leukemia and assessed the relationship between venetoclax exposure and clinical response for venetoclax in combination with either a hypomethylating agent (HMA) or low-dose cytarabine (LDAC). A total of 771 patients who received venetoclax from 5 Phase 1-3 studies were included in the popPK model. Exposure-response analyses included data from 575 patients for venetoclax/placebo plus HMA and 279 patients for venetoclax/placebo plus LDAC. The popPK model successfully characterized venetoclax plasma concentrations over time and confirmed venetoclax exposure did not vary significantly with age, weight, sex, mild to moderate hepatic impairment, or mild to severe renal impairment. Asian patients had 67% higher mean relative bioavailability than non-Asian patients, however the range of exposures in Asian patients was similar to non-Asian patients. For all efficacy endpoints with both treatment combinations, efficacy was higher in the venetoclax treatment groups compared with the respective control arm of placebo plus azacitidine or LDAC. Within patients who received venetoclax, no significant exposure-efficacy relationships were identified for either treatment combination, indicating that the beneficial effects of venetoclax were already maximized in the dose ranges studied. There was no apparent effect of venetoclax exposure on treatment-emergent Grade ≥3 thrombocytopenia or infections for either combination. Rates of treatment-emergent Grade ≥3 neutropenia were higher in the venetoclax treatment arms compared with the respective control arms; however, within patients who received venetoclax, there was only a shallow relationship or no apparent relationship with venetoclax exposure for venetoclax plus HMA or LDAC, respectively. Along with the efficacy and safety data previously published, the exposure-response analyses support the venetoclax dose regimens of 400 mg once daily (QD) plus HMA and 600 mg QD plus LDAC in treatment-naïve AML patients who are ineligible for intensive chemotherapy.

Population pharmacokinetics of paritaprevir, ombitasvir, dasabuvir, ritonavir and ribavirin in hepatitis C virus genotype 1 infection: analysis of six phase III trials.

AIM: The aim of the current study was to characterize the population pharmacokinetics of a triple direct-acting antiviral (DAA) regimen (3D) (ombitasvir, paritaprevir-ritonavir and dasabuvir) and adjunctive ribavirin, and estimate covariate effects in a broad spectrum of subjects with hepatitis C virus (HCV) genotype 1 infection. METHODS: Pharmacokinetic data from six phase III studies and one phase II study in subjects receiving the currently approved doses of the 3D ± ribavirin regimen for treating HCV genotype 1 infection for 12 weeks or 24 weeks were characterized using separate population pharmacokinetic models, built using each component of the regimen from nonlinear mixed-effects methodology in NONMEM 7.3. In the models, demographic and clinical covariates were tested. Models were assessed via goodness-of-fit plots, visual predictive checks and bootstrap evaluations. RESULTS: The population pharmacokinetic models for each component of the 3D ± ribavirin regimen (DAAs and ritonavir, n = 2348) and ribavirin (n = 1841) adequately described their respective plasma concentration-time data. Model parameter estimates were precise and robust, and all models showed good predictive ability. Significant covariate effects associated with apparent clearance and volume of distribution included age, body weight, gender, cirrhosis, HCV subtype, opioid or antidiabetic agent use, and creatinine clearance. CONCLUSION: The population pharmacokinetics of the 3D ± ribavirin regimen components in HCV-infected patients were characterized using phase II and III HCV clinical trial data. Although several statistically significant covariates were identified, their effects were modest and not clinically meaningful to necessitate dose adjustments for any component of the 3D regimen.

Pharmacokinetics and Exposure-Response Analyses to Support Dose Selection of Upadacitinib in Crohn's Disease.

Upadacitinib, a selective Janus kinase inhibitor, is the first orally administered therapy approved for the treatment of Crohn's disease (CD). This work characterized the pharmacokinetics of upadacitinib in CD patients and evaluated the relationships between upadacitinib steady-state plasma exposures and efficacy as well as safety parameters during the 12-week induction and the 52-week maintenance periods, to provide dosing recommendations for the treatment of CD. Upadacitinib pharmacokinetics in CD patients administered the extended-release formulation were consistent with patient populations in other approved indications. None of the evaluated CD-specific patient characteristics (e.g., disease location and prior gastrointestinal surgeries) had a meaningful impact on upadacitinib pharmacokinetics. Exposure-response analyses during 12-week induction treatment showed that response across all evaluated efficacy end points were approaching a plateau at median plasma exposures associated with 45 mg QD. Analyses for the maintenance period demonstrated that 30 mg QD is predicted to provide an additional 8% to 10% benefit for endoscopic response and endoscopic remission compared with 15 mg QD in patients who failed biologics. The analyses for safety showed a statistically significant relationship between increasing upadacitinib plasma exposures and the percentage of patients experiencing >2 g/dL decrease in hemoglobin from Baseline during induction and showed shallow relationships for serious infections and herpes zoster during the maintenance period. These results demonstrated adequate absorption of the extended-release formulation of upadacitinib in CD patients. The exposure-response analyses confirmed that 45 mg QD dose maximized efficacy as induction treatment and supported the selection of 15 mg QD or 30 mg QD as the maintenance doses.

Population pharmacokinetics and exposure-response analyses for efficacy and safety of upadacitinib in patients with axial spondyloarthritis.

Upadacitinib is an orally administered, selective, Janus kinase inhibitor that is approved for several auto-immune conditions, such as axial spondyloarthritis, an inflammatory rheumatic disease that includes ankylosing spondylitis (AS) and non-radiographic axial spondyloarthritis (nr-axSpA). The approvals of upadacitinib for the treatment of AS and nr-axSpA were based on the safety and efficacy data for upadacitinib 15 mg once-daily compared to placebo from the SELECT-AXIS 1 and SELECT-AXIS 2 studies. Population pharmacokinetic analyses based on data from 244 patients with axSpA showed that the pharmacokinetics of upadacitinib were comparable in subjects with AS and nr-axSpA. Exposure-response relationships were characterized for key efficacy and safety end points using data from 482 patients with axSpA. The exposure-response analyses for efficacy based on Assessment of SpondyloArthritis International Society (ASAS)20 and ASAS40 responses at week 14, showed a clear differentiation from placebo with no evidence of increased responses with increasing upadacitinib plasma exposures. There were no clear exposure-response trends observed for safety end points that included serious infections, herpes zoster, pneumonia, lymphopenia (grade ≥3), neutropenia (grade ≥3), or a greater than 2 g/dL decrease in hemoglobin from baseline through week 14. The exposure-response analyses for efficacy and safety presented here supported the favorable benefit-risk profile with the use of upadacitinib 15 mg once-daily for the treatment of axSpA.

Cedirogant Population Pharmacokinetics and Pharmacodynamic Analyses of Interleukin-17A Inhibition in Two Phase 1 Studies in Healthy Participants and Participants with Moderate to Severe Psoriasis.

Cedirogant (ABBV-157) is an orally bioavailable inverse agonist of retinoic acid-related orphan receptor gamma thymus. Data from 2 Phase 1 studies were used to characterize cedirogant pharmacokinetics and evaluate target engagement. Cedirogant plasma concentrations and ex vivo interleukin 17A (IL-17A) concentrations from healthy participants and participants with moderate to severe psoriasis (PsO) were analyzed in a population pharmacokinetic and pharmacodynamic modeling framework to characterize cedirogant pharmacokinetics following single and multiple doses and assess ex vivo IL-17A inhibition in relation to cedirogant exposure. Cedirogant population pharmacokinetics were best described by a 2-compartment pharmacokinetic model with delayed absorption and an enzyme turnover compartment to describe cytochrome P450 3A autoinduction. The pharmacokinetics of cedirogant were comparable between healthy participants and participants with PsO. Cedirogant steady-state average and maximum plasma concentrations were predicted to be 7.56 and 11.8 mg/L, respectively, for participants with PsO for the 375 mg once-daily regimen on Day 14. The apparent clearance and apparent volume of distribution for cedirogant were estimated to be 24.5 L/day and 28.2 L, respectively. A direct maximum inhibition model adequately characterized the exposure-response relationship of cedirogant and ex vivo IL-17A inhibition, indicating no temporal delay between exposure and response with a saturable inhibition of IL-17A. Model-estimated half-maximal inhibitory concentration and maximum inhibition values for cedirogant inhibition of ex vivo IL-17A were 0.56 mg/L and 0.76, respectively. The established relationship between cedirogant exposure and biomarker effect supported dose selection for the Phase 2 dose-ranging study in patients with PsO.

Upadacitinib Population Pharmacokinetics and Exposure-Response Relationships in Ulcerative Colitis Patients.

BACKGROUND AND OBJECTIVE: Upadacitinib, an oral selective and reversible Janus kinase (JAK) inhibitor, showed favorable efficacy and safety in patients with moderate-to-severe ulcerative colitis (UC). The objective was to characterize upadacitinib pharmacokinetics in UC patients across Phase 2b and 3 trials and evaluate the relationships between upadacitinib plasma exposures and key efficacy or safety endpoints. METHODS: Population pharmacokinetics and exposure-response analyses were performed to characterize upadacitinib pharmacokinetics in UC patients and evaluate the relationships between plasma exposures and key efficacy or safety endpoints at the end of 8-week induction and 52-week maintenance periods. Data from 1234 UC patients from Phase 2 and 3 induction trials and 449 UC patients from a Phase 3 maintenance trial were used for these analyses. Additionally, data from patients with rheumatoid arthritis, atopic dermatitis, Crohn's disease, and healthy volunteers were used in the pharmacokinetics analysis. Quartile plots and logistic regression models were used to evaluate the exposure-response relationships across upadacitinib doses of 7.5-45 mg once daily (QD) for induction and 15-30 mg QD for maintenance. RESULTS: Upadacitinib plasma exposures were dose-proportional in UC patients across the evaluated dose range. Upadacitinib pharmacokinetics in UC were consistent between the induction and maintenance periods, and with other patient populations. Upadacitinib plasma exposures associated with the 45 mg QD induction dose maximized efficacy for Week 8 clinical and endoscopic endpoints. Plasma exposures associated with upadacitinib 30 mg maintenance dose provided additional incremental benefit compared to 15 mg QD for Week 52 key clinical and endoscopic endpoints. No trends were observed in the evaluated safety events with increasing plasma exposures at the end of induction or maintenance periods. CONCLUSION: These analyses supported selection of upadacitinib UC induction and maintenance doses. TRIAL REGISTRATION: Data from studies NCT02819635 and NCT03653026 were included in these analyses.

Exposure-Response Model With Time-Varying Predictors to Estimate the Effects of Veliparib in Combination With Carboplatin/Paclitaxel and as Monotherapy: Veliparib Phase 3 Study in BRCA-Mutated Advanced Breast Cancer (BROCADE3) Trial.

BRCA-Mutated Advanced Breast Cancer (BROCADE3) is a phase 3 study, evaluating veliparib in combination with carboplatin/paclitaxel with continuation as monotherapy if carboplatin/paclitaxel is discontinued in patients with germline BRCA1/2 mutation-associated, advanced human epidermal growth factor receptor 2-negative breast cancer. The objective of the current analysis was to characterize the veliparib exposure-response relationships for efficacy (progression-free survival [PFS]) and safety in this study. Exposure-efficacy analyses of PFS were conducted using Kaplan-Meier plots and cox proportional hazards (CPH) models using treatment alone or both treatment and exposure as time-dependent predictors to estimate the effect of veliparib in combination with carboplatin/paclitaxel and as monotherapy. The cox proportional hazards model with only treatment as the time-varying predictor estimated a statistically significant benefit of veliparib monotherapy compared to placebo monotherapy (hazard ratio, 0.49; 95%CI, 0.33-0.73) and a modest, non-statistically significant benefit (hazard ratio, 0.81; 95%CI, 0.62-1.05) of adding veliparib to carboplatin/paclitaxel. Inclusion of exposure as an additional time-varying predictor in the cox proportional hazards model indicated a flat exposure-response relationship between the veliparib exposure and PFS when veliparib was administered in combination with carboplatin/paclitaxel or as monotherapy. The exposure-safety analysis did not reveal any meaningful exposure-dependent trend in the incidence of adverse events of interest. These analyses support the dose regimen of veliparib (120 mg twice daily) in combination with carboplatin/paclitaxel and continuation of veliparib (300-400 mg twice daily) as monotherapy if carboplatin/paclitaxel were discontinued before disease progression in this patient population. This study is registered with ClinicalTrials.gov with a registration ID: NCT02163694.

A Population Pharmacokinetic Meta-Analysis of Veliparib, a PARP Inhibitor, Across Phase 1/2/3 Trials in Cancer Patients.

Veliparib (ABT-888) is a poly(ADP-ribose) polymerase inhibitor in development for the treatment of high-grade ovarian cancer or BRCA-mutated breast cancer in combination with carboplatin and paclitaxel. The population pharmacokinetics of veliparib were characterized using combined data from 1470 adult subjects with ovarian cancer, breast cancer, or other solid tumors enrolled in 6 phase 1 studies, 1 phase 2 study, and 2 phase 3 studies of veliparib oral doses of 10 to 400 mg twice daily as monotherapy or in combination with chemotherapy. A 1-compartment model with linear clearance and first-order absorption best characterized veliparib pharmacokinetics. The predicted apparent oral clearance (CL/F) and volume of distribution (Vc /F) were 479 L/day and 152 L, respectively. The significant covariates in the final model included albumin, creatinine clearance, strong inhibitors of cytochrome P450 (CYP) 2D6, and sex on CL/F and albumin, body weight, and sex on Vc /F. Mild and moderate renal impairment increased veliparib median (95%CI) steady-state AUC (AUCss ) by 27.3% (23.7%-30.9%) and 65.4% (56.0%-75.5%), respectively, compared with normal renal function. Male subjects had 16.5% (7.53%-23.9%) lower AUCss compared with female subjects and coadministration with strong CYP2D6 inhibitors increased AUCss by 13.0% (6.11%-20.8%). Race, age, region, cancer type, or enzyme (CYP3A4, CYP2C19) or transporter (P-glycoprotein, multidrug and toxin extrusion protein 1/2, organic cation transporter 2) inhibiting/inducing comedications were not found to significantly impact veliparib pharmacokinetics. Other than baseline creatinine clearance and hence renal impairment effect on veliparib clearance, no other covariates had a clinically meaningful effect on veliparib exposure warranting dose adjustment.

Population Pharmacokinetics of Glecaprevir/Pibrentasvir in HCV-infected Japanese Subjects in Phase 3 CERTAIN-1 and CERTAIN-2 Trials.

Glecaprevir (GLE)/pibrentasvir (PIB) 300 mg/120 mg once daily (Mavyret/Maviret) is an all-oral, pangenotypic, interferon- and ribavirin-free combination regimen approved for the treatment of chronic hepatitis C virus (HCV) infection. The objective of the current analyses was to characterize the pharmacokinetics (PK) of GLE/PIB in HCV-infected Japanese patients. Data from 332 subjects enrolled in 2 Japan phase 3 trials, CERTAIN-1 and CERTAIN-2, were used in the analyses. Pharmacokinetics of GLE/PIB were characterized using a nonlinear mixed-effects modeling. The analyses evaluated the impact of covariates (concomitant medications and demographic and clinical covariates such as renal impairment, effect of cirrhotic status) on GLE/PIB PK. GLE and PIB PK were described by 1- and 2-compartment models, respectively. Presence of cirrhosis, age, and body weight were identified as significant covariates on GLE/PIB PK. A trend toward higher GLE and PIB exposures in older patients and higher PIB exposures in heavier patients was observed; however, these increases were not considered clinically meaningful. GLE and PIB exposures were higher in HCV-infected subjects with cirrhosis (Child-Pugh A; GLE area under the plasma concentration-time curve was 160% higher, and PIB area under the plasma concentration-time curve was 21% higher) compared to subjects without cirrhosis. Renal function (including subjects with end-stage renal disease with dialysis) had no impact on GLE or PIB exposures. The GLE/PIB dose was well tolerated in the Japanese population, and no dose adjustment is needed for the evaluated intrinsic and extrinsic factors.

Pharmacokinetics of Risankizumab in Asian Healthy Subjects and Patients With Moderate to Severe Plaque Psoriasis, Generalized Pustular Psoriasis, and Erythrodermic Psoriasis.

Risankizumab, a humanized monoclonal antibody that targets interleukin-23 p19 subunit, was developed for the treatment of psoriasis. This work characterizes risankizumab pharmacokinetics in Japanese and Chinese healthy subjects compared with white healthy subjects and in Japanese patients with moderate to severe plaque psoriasis, generalized pustular psoriasis, or erythrodermic psoriasis. A phase 1, single-dose study evaluated risankizumab pharmacokinetics and safety/tolerability in healthy white (18 and 300 mg subcutaneous [SC]), Japanese (18, 90, and 300 mg SC and 200, 600, and 1200 mg intravenous [IV]), and Chinese (18, 90, and 300 mg SC) subjects; pharmacokinetic data were analyzed using noncompartmental methods. Risankizumab pharmacokinetic data from phase 2/3 studies in Japanese patients with plaque psoriasis, generalized pustular psoriasis, or erythrodermic psoriasis following multiple SC doses of 75 mg or 150 mg were analyzed using a population pharmacokinetic approach along with data from the phase 1 and global phase 1 to 3 studies. Risankizumab plasma exposures (peak plasma concentration and area under the concentration-time curve) were approximately dose-proportional across 18- to 300-mg SC or 200- to 1200-mg IV doses. Risankizumab terminal elimination half-life (harmonic mean 27-34 days) was comparable across doses and ethnicities. Risankizumab exposures were approximately 20% to 30% higher in Japanese and Chinese healthy subjects compared with white healthy subjects or in Japanese patients compared with non-Japanese patients. After accounting for body-weight differences, risankizumab exposures were comparable across ethnicities. Overall, there was no ethnic impact on risankizumab pharmacokinetics, and the small difference in exposure due to body weight has no clinical relevance.

Effects of Mild and Moderate Renal Impairment on Ombitasvir, Paritaprevir, Ritonavir, Dasabuvir, and Ribavirin Pharmacokinetics in Patients with Chronic HCV Infection.

BACKGROUND AND AIMS: Ombitasvir, paritaprevir (given with low-dose ritonavir), and dasabuvir are direct-acting antivirals (DAAs) used with or without ribavirin for the treatment of chronic hepatitis C virus (HCV) infection. The objective of this analysis was to evaluate the effect of renal function as determined by creatinine clearance (CrCL) on the pharmacokinetics of the DAAs, ritonavir, and ribavirin in HCV genotype 1-infected patients with or without cirrhosis. METHODS: Total exposure, measured by area under the plasma concentration-time curve (AUC), was generated for the DAAs, ritonavir, and ribavirin using population pharmacokinetic modeling of data (N = 2093 patients) from 6 Phase 3 studies and 1 Phase 2 study. The effect of CrCL on the AUC values of each DAA, ritonavir, and ribavirin was separately evaluated and adjusted for any significant patient-specific covariates including, age, sex, body weight, cirrhosis, and Asian race in multiple linear regression analysis. Using the final models, AUC values were predicted for patients with normal renal function (CrCL = 105 mL/min), mild renal impairment (CrCL = 75 mL/min) and moderate renal impairment (CrCL = 45 mL/min). RESULTS: CrCL was not a statistically significant predictor of DAA or ritonavir AUC values. Age, sex, and cirrhosis were significant covariates for the AUC values of all the DAAs and body weight was a significant covariate for the AUC values of ombitasvir and dasabuvir. Asian race was significant only for dasabuvir. Only age and sex were statistically significant predictors for the AUC values of ritonavir. CrCL showed a significant relationship with the ribavirin AUC values, consistent with ribavirin's renal excretion. Age, sex, body weight, and cirrhosis were also significant covariates for the AUC values of ribavirin. The DAA and ritonavir AUC values were comparable (≤10 % difference) among different levels of renal function, while ribavirin AUC values were up to 17 % higher in mild/moderate renal impairment compared with normal renal function. CONCLUSIONS: No dose adjustments are needed for the 3D regimen in HCV genotype-1 infected patients with mild or moderate renal impairment. Ribavirin doses should be adjusted for renal impairment as recommended in the ribavirin label.

Impact of Venetoclax Exposure on Clinical Efficacy and Safety in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia.

BACKGROUND: Venetoclax is a selective, potent, first-in-class B-cell lymphoma-2 inhibitor that restores apoptosis in cancer cells and has demonstrated efficacy in a variety of hematological malignancies. OBJECTIVE: The objective of this research was to characterize the relationship between venetoclax exposures and efficacy and safety in patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). METHODS: A total of 272 and 338 patients from four clinical studies were pooled for the exposure-efficacy and exposure-safety analyses, respectively. Demographics, baseline disease characteristics, and select co-medications were evaluated for their impact on efficacy (lymphocytes, tumor size, objective response [OR]) and safety (neutropenia and infection). RESULTS: Higher venetoclax concentrations led to a more rapid decrease in lymphocyte counts and tumor size, which translated into patients more rapidly achieving OR. The 17p deletion somatic mutation was not identified, in any of the analyses, to affect the responsiveness of patients to venetoclax. Model-based simulations of lymphocyte counts and tumor size estimated an OR rate (ORR) of 84.8 % (95 % confidence interval 81.5-88.0 %) at a venetoclax dosage of 400 mg daily, with minimal increase in ORR at higher doses. The safety analyses of the adverse events (grade 3 or higher) of neutropenia and infection indicated that higher average venetoclax concentrations were not associated with an increase in adverse events. CONCLUSIONS: The exposure-response analyses indicated that a venetoclax dosage regimen of 400 mg daily results in a high (>80 %) probability of achieving OR in R/R CLL/SLL patients, with minimal probability of increasing neutropenia or infection with higher exposures.

Pharmacokinetics and exposure-efficacy relationship of adalimumab in pediatric patients with moderate to severe Crohn's disease: results from a randomized, multicenter, phase-3 study.

BACKGROUND: Adalimumab, a fully human monoclonal antibody (IgG1κ) to tumor necrosis factor, has shown benefit in the treatment of inflammatory bowel disease. The purpose of this analysis was to evaluate the pharmacokinetics (PK) and the serum concentration-efficacy relationship of adalimumab in pediatric patients with moderate-to-severe Crohn's disease. METHODS: The safety, efficacy, and PK of adalimumab was evaluated in a phase-3, randomized, double-blind, 52-week study (IMAgINE-1, N = 192), which had a 4-week open-label induction phase (dose was determined by patient weight) followed by a 48-week double-blind maintenance phase (standard and low-dose arms, drug given every other week). Trough serum adalimumab (baseline, weeks 2, 4, 16, 26, and 52) and anti-adalimumab antibody measurements (baseline, weeks 16, 26, and 52) were collected. Disease activity was assessed using the Pediatric Crohn's Disease Activity Index. RESULTS: At week 52, adalimumab trough concentrations (mean ± SD) were higher for patients in the standard-dose (9.48 ± 5.61 µg/mL) compared with the low-dose (3.51 ± 2.21 µg/mL) arm. In patients whose doses were increased from every other week to weekly, higher trough concentrations were observed after dose escalation. Higher body weight, baseline C-reactive protein, and lower baseline albumin levels were associated with greater clearance of adalimumab. An exposure (serum concentration)-efficacy relationship was observed, in which higher concentrations of adalimumab were associated with greater rates of remission. CONCLUSIONS: This study is the first to describe the PK of adalimumab in pediatric patients with moderate-to-severe Crohn's disease. A positive association between serum adalimumab concentration and remission/response was identified.