Population pharmacokinetic and exposure-response analyses of elotuzumab plus pomalidomide and dexamethasone for relapsed and refractory multiple myeloma.

PURPOSE: Elotuzumab plus pomalidomide/dexamethasone (E-Pd) demonstrated efficacy and safety in relapsed and refractory multiple myeloma (RRMM). The clinical pharmacology of elotuzumab [± lenalidomide/dexamethasone (Ld)] was characterized previously. These analyses describe elotuzumab population pharmacokinetics (PPK), the effect of Pd, and assess elotuzumab exposure-response relationships for efficacy and safety in patients with RRMM. METHODS: A previously established PPK model was updated with E-Pd data from the phase 2 ELOQUENT-3 study (NCT02654132). The dataset included 8180 serum concentrations from 440 patients with RRMM from 5 clinical trials. Elotuzumab PK parameter estimates were used to generate individual daily time-varying average concentrations (daily Cavg) for multi-variable time-to-event exposure-response analyses of progression-free survival (PFS) and time to the first occurrence of grade 3 + adverse events (AEs) in RRMM. RESULTS: Elotuzumab PK were well-described by a two-compartment model with parallel linear and Michaelis-Menten elimination from the central compartment (Vmax) and non-renewable target-mediated elimination from the peripheral compartment (Kint). Co-administration with Pd resulted in a 19% and 51% decrease in elotuzumab linear clearance and Kint, respectively, versus Ld; steady-state exposures were similar. Vmax increased with increasing serum M-protein. Hazard ratios (95% confidence intervals) for daily Cavg were 0.9983 (0.9969-0.9997) and 0.9981 (0.9964-0.9998) for PFS and grade 3 + AEs, respectively. CONCLUSIONS: The PPK model adequately described the data and was appropriate for determining exposures for exposure-response analyses. There were no clinically relevant differences in elotuzumab exposures between Pd and Ld backbones. In ELOQUENT-3, increasing elotuzumab daily Cavg prolonged PFS without increasing grade 3 + AEs.

Benefit-risk assessment of nivolumab 240 mg flat dose relative to 3 mg/kg Q2W regimen in Japanese patients with advanced cancers.

Nivolumab 3 mg/kg every 2 weeks (Q2W) has been approved in Japan for various cancers; however, use of a flat dose is expected to simplify dosing and administration. A quantitative clinical pharmacology approach was used to assess the benefit-risk profile of nivolumab 240 mg Q2W relative to the approved dose of nivolumab 3 mg/kg Q2W in Japanese patients. Three exposure-response safety analyses were performed for adverse events that led to discontinuation/death, were grade 3 or higher, and were immune-mediated and grade 2 or higher for Japanese patients diagnosed with one of multiple tumor types. Exposure-response analyses of efficacy were evaluated for overall survival and objective response rate. Exposures of nivolumab 240 mg Q2W were 37% higher than those of nivolumab 3 mg/kg Q2W in Japanese patients across the tumor types analyzed. Predicted safety profiles at the two doses differed by less than 2% across tumor types for adverse events leading to discontinuation/death, adverse events of grade 3 or higher, or immune-mediated adverse events of grade 2 or higher. In addition, the predicted 1-year and 2-year overall survival rates, the mean overall survival and the objective response rates were comparable between the doses regardless of the tumor type analyzed. Overall, these results demonstrated that the benefit-risk of nivolumab 240 mg Q2W was comparable to that of the previously approved 3 mg/kg Q2W dosing regimen, and was the basis for the approval of the 240 mg Q2W as an alternative dosing regimen for treatment in Japanese patients across multiple tumor types.

Population Pharmacokinetic Analysis of Daclatasvir, Asunaprevir, and Beclabuvir Combination in HCV-Infected Subjects.

A fixed-dose combination of daclatasvir (pangenotypic NS5A inhibitor), asunaprevir (NS3/4A protease inhibitor), and beclabuvir (nonnucleoside NS5B inhibitor) was approved for hepatitis C virus treatment in Japan. The objectives of the analyses were to develop the daclatasvir, asunaprevir, and beclabuvir population pharmacokinetic models for the combination regimen. First, an original population pharmacokinetic model was developed using the data in non-Japanese hepatitis C virus-infected subjects. The model was subsequently updated after a phase 3 study in Japanese hepatitis C virus-infected subjects was available. A total of 11,382, 11,300, and 10,728 pharmacokinetic records from 1,228 subjects were included for daclatasvir, asunaprevir, and beclabuvir in the updated model, respectively. Daclatasvir and beclabuvir pharmacokinetics (PK) were described by a 1-compartment model with linear elimination and asunaprevir PK was described by 2-compartment model with linear elimination. Cirrhosis, baseline, and time-varying ALT were significant covariates on asunaprevir apparent oral clearance. Asian subjects had greater asunaprevir and beclabuvir exposures than white subjects. The effects of all covariates on daclatasvir PK were modest and not considered clinically significant. With the exception of race on asunaprevir and beclabuvir PK, no other parameters for daclatasvir, asunaprevir and beclabuvir population PK models were meaningfully impacted during the refinement with Japanese subjects.

Population pharmacokinetics analysis of nivolumab in Asian and non-Asian patients with gastric and gastro-esophageal junction cancers.

PURPOSE: Nivolumab monotherapy provided clinically meaningful antitumor activity in Asian and non-Asian patients with chemotherapy-refractory gastric cancer (GC) or gastro-esophageal junction cancer (GEJC) in the ATTRACTION-2 and CheckMate 032 studies, respectively. This analysis assessed the population pharmacokinetics (PopPK) of nivolumab, the impact of covariates on pharmacokinetics (PK), and the PK of nivolumab flat dosing in GC/GEJC using samples from these studies. METHODS: PopPK analyses were conducted using data from 1302 patients with solid tumors, including 387 patients with GC/GEJC who had received nivolumab 3 mg/kg once every 2 weeks (Q2W). The impact of covariates on nivolumab PK was assessed in the full model. Nivolumab exposures following a flat dose of 240 mg Q2W in patients with GC/GEJC were simulated and compared with those of 3 mg/kg Q2W. RESULTS: Nivolumab PK was described using a 2-compartment, zero-order intravenous infusion and time-varying clearance (CL) model. Baseline CL in patients with GC/GEJC was ~ 33% greater than in patients with non-small cell lung cancer (NSCLC) in second line or subsequent lines of treatment (2L+). The effect of race was not clinically relevant (< 20% difference). Nivolumab exposures following 240 mg Q2W were similar to 3 mg/kg Q2W in non-Asian patients and 46% higher in Asian patients due to lower body weight. CONCLUSIONS: Nivolumab CL was increased in GC/GEJC relative to NSCLC 2L+. Higher nivolumab exposures achieved with 240 mg Q2W in Asian patients are predicted to be below the acceptable safety margin, supporting the use of a flat dose in both patient populations.

Safety Exposure-Response Analysis for Daclatasvir, Asunaprevir, and Beclabuvir Combinations in HCV-Infected Subjects.

The combination regimen of daclatasvir, asunaprevir, and beclabuvir has been developed for the treatment of hepatitis C virus infection. The objectives of this analysis were to characterize the relationship between the exposures of the daclatasvir, asunaprevir, and beclabuvir regimen and liver-related laboratory elevations (Grade 3 or 4 alanine aminotransferase [ALT] and total bilirubin [Tbili]), and to evaluate the impact of selected covariates on the exposure-response relationships. The exposure-response analysis was performed with data from 1 phase 2 and 3 phase 3 studies in hepatitis C virus-infected subjects. The probability of liver-related laboratory elevations were modeled using linear logistic regression. Selected covariates were tested using a forward-addition and backward-elimination approach. The final model for ALT elevation included Asian race, body weight in non-Asian subjects, and asunaprevir exposure. The final model for Tbili elevation included Asian race, fibrosis score (F0-F3 or F4) and asupanprevir exposure. Asian subjects had greater the Grade 3 or 4 ALT and Tbili elevation rates than non-Asians. The Grade 3 or 4 ALT elevation rate increased with decreasing body weight in non-Asian subjects. Subjects with F4 fibrosis score had a higher rate of Grade 3 or 4 Tbili elevation compared to subjects with F0 to F3 fibrosis score. Higher asunaprevir exposure was associated with increases in Grade 3 or 4 ALT and Tbili elevation rates; however, the impact on the ALT elevation was not clinically relevant and the effect on Tbili elevation was smaller than the other significant covariates.

Exposure-Response (Efficacy) Analysis of Daclatasvir and Asunaprevir in Japanese Patients With Hepatitis C Virus Infection.

The treatment of hepatitis C virus (HCV) infection has been revolutionized by the development of all-oral combination regimens of direct-acting antiviral agents. The current analysis characterized the relationship between exposures of daclatasvir (DCV; tablets) and asunaprevir (ASV; capsules) and sustained virologic response (SVR) in Japanese patients who are HCV genotype (GT) 1b nonresponders to pegylated interferon (IFN) α/ribavirin or IFNß/ribavirin, and IFN-based therapy-ineligible naive/intolerant patients receiving DCV and ASV, and provided insight into patient covariates that were most closely associated with efficacy. The relationship between the probability of achieving SVR at 12 weeks after treatment (SVR12) and average steady-state plasma concentrations estimated from population pharmacokinetic models for DCV and ASV is described using a logistic regression model with data from a phase 2 and a phase 3 study in Japanese patients infected with HCV GT 1b (N=265). The functional form characterization, which describes a relationship between DCV and ASV average steady-state plasma concentrations and SVR12, as well as covariate identification (demographic, laboratory, and prognostic and treatment covariates) were investigated during model development. The presence of the signature nonstructural protein 5A Y93H mutation at baseline was the only significant parameter of SVR12 in the final exposure-response model. Model evaluation plots demonstrate that the final model was able to predict the observed SVR rates. Exposure-response analysis supports the clinical utility of the combination regimen of 60-mg once-daily DCV and 100-mg twice-daily ASV in Japanese patients infected with HCV GT 1b.

Population Pharmacokinetic Analysis for Daclatasvir and Asunaprevir in Japanese Subjects With Chronic Hepatitis C Virus Infection.

Daclatasvir is a nonstructural protein 5A replication complex inhibitor, and asunaprevir is a nonstructural protein 3 protease inhibitor for hepatitis C virus (HCV). In 2014, the combination therapy of daclatasvir and asunaprevir received the first global approval in Japan as the first nonribavirin, all-oral therapy for HCV treatment. The population pharmacokinetics (popPK) of daclatasvir and asunaprevir were characterized by nonlinear mixed-effects modeling using 3801 and 2626 concentration data from 336 and 265 Japanese HCV subjects, respectively. The plasma pharmacokinetic profiles of daclatasvir and asunaprevir were described by a 1-compartment model. Parameter estimates (interindividual variability) of daclatasvir apparent clearance (CL/F) and apparent volume of the central compartment (V/F) were 5.29 L/h (39.4%) and 64.2 L (38.1%). The effects of all statistically significant covariates on daclatasvir PK parameters were within or overlapped the 80% to 125% boundaries, suggesting a lack of clinical relevance. Parameter estimates (interindividual variability) of asunaprevir CL/F and V/F were 52.1 L/h (41.5%) and 75.1 L (93.4%), respectively. Baseline and time-varying aspartate aminotransferase (AST) and cirrhosis on CL/F and formulation (soft-gel capsule or tablet) on F were included as significant covariates in the asunaprevir popPK model. The effects of all covariates exceeded the 80% to 125% boundaries, indicating that the asunaprevir soft-gel capsule had higher bioavailability than the tablet and that asunaprevir exposure increased with cirrhosis and increasing baseline and time-varying AST values. The popPK models adequately described the PK profiles of daclatasvir and asunaprevir in Japanese HCV subjects.

Population Pharmacokinetic Analysis of Asunaprevir in Subjects with Hepatitis C Virus Infection.

INTRODUCTION: Asunaprevir (ASV) is a potent, pangenotypic, twice-daily hepatitis C virus (HCV) NS3 inhibitor indicated for the treatment of chronic HCV infection. METHODS: A population pharmacokinetic (PPK) model was developed using pooled ASV concentration data from 1239 HCV-infected subjects who received ASV either as part of the DUAL regimen with daclatasvir or as part of the QUAD regimen with daclatasvir and peg-interferon/ribavirin. RESULTS: A two-compartment model with first-order elimination from the central compartment, an induction effect on clearance, and an absorption model consisted of zero-order release followed by first-order absorption adequately described ASV PK after oral administration. A typical value for ASV clearance (CL/F) was 50.8 L/h, increasing by 43% after 2 days to a CL/F of 72.5 L/h at steady-state, likely due to auto-induction of cytochrome P450 3A4 (CYP3A4). Factors indicative of hepatic function were identified as key influential covariates on ASV exposures. Subjects with cirrhosis had an 84% increase in ASV area under the concentration time curve (AUC) and subjects with baseline aspartate aminotransferase (AST) above 78 IU/L had a 58% increase in area under the concentration time curve (AUC). Asians subjects had a 46% higher steady-state AUC relative to White/Caucasian subjects. Other significant covariates were formulation, age, and gender. CONCLUSION: The current PPK model provided a parsimonious description of ASV concentration data in HCV-infected subjects. Key covariates identified in the model help explain the observed variability in ASV exposures and may guide clinical use of the drug. FUNDING: Bristol-Myers Squibb.

Population Pharmacokinetic Analysis of Daclatasvir in Subjects with Chronic Hepatitis C Virus Infection.

BACKGROUND AND OBJECTIVE: Daclatasvir is a potent, pangenotypic once-daily hepatitis C virus (HCV) NS5A inhibitor that is approved for the treatment of chronic HCV infection. The objective of this analysis was to characterize the pharmacokinetics of daclatasvir in subjects with chronic HCV infection. METHODS: A population pharmacokinetic (PPK) model was developed to evaluate effects of covariates on daclatasvir pharmacokinetics in subjects with chronic HCV infection (n = 2149 from 11 studies). All significant demographic, laboratory, prognostic and treatment covariates (p < 0.05) from univariate screening were included in the full model. The final model was reached by backward elimination (p < 0.001) and simulations were performed to further evaluate the effects of covariates on daclatasvir exposures. The plasma pharmacokinetics of daclatasvir was described by a two-compartment model with linear elimination. Absorption was modeled as a zero-order release followed by a first-order absorption into the central compartment. RESULTS: The typical value of apparent clearance (CL/F) was 5.7 L/h (1.58% relative standard error [RSE]) and of apparent volume of the central compartment (V c/F) was 58.6 L (2.00% RSE). Modest inter-individual variability was estimated for CL/F (35.1%) and V c/F (29.5%). Statistically significant covariates in the final model were sex, race, virus genotype, baseline creatinine clearance, and alanine aminotransferase (ALT) on CL/F and sex, race, and body weight on V c/F. Covariate effects demonstrated a 30% higher area under the plasma concentration-time curve at steady state (AUCss) in female subjects; effects of all other covariates were <16%. CONCLUSIONS: The model adequately described the daclatasvir pharmacokinetics and estimated relatively small covariate effects. Considering the exposure range for the therapeutic dose of daclatasvir 60 mg once daily and the favorable safety profile, the small difference in exposures due to these covariates is not considered clinically relevant.