Trastuzumab Deruxtecan Dosing in Human Epidermal Growth Factor Receptor 2-Positive Gastric Cancer: Population Pharmacokinetic Modeling and Exposure-Response Analysis.

This study evaluated the benefit/risk of trastuzumab deruxtecan (T-DXd) 6.4 mg/kg in patients with human epidermal growth factor receptor 2 (HER2)-positive gastric cancer using pharmacometrics. A population pharmacokinetic (PopPK) model was developed using data from patients with gastric cancer, breast cancer, or other tumors in T-DXd clinical trials, primarily conducted in Asia. Post hoc model-estimated pharmacokinetic metrics were used in exposure-efficacy (objective response rates, ORRs) and exposure-safety analyses. The PopPK analysis included 808 patients (217 with gastric cancer, 512 with breast cancer, and 79 with other cancers). In gastric cancer, the T-DXd 6.4 mg/kg steady-state exposure metrics were lower compared with 6.4 mg/kg in breast cancer, but were similar to 5.4 mg/kg in breast cancer. Tumor type was selected as a significant covariate on T-DXd clearance. In exposure-efficacy analysis among 160 patients with gastric cancer, the T-DXd steady-state minimum concentration was associated with a confirmed ORR in univariate logistic regression analysis (P = .023). The model-predicted confirmed ORRs in gastric cancer were 36.0% (90%CI 29.3% to 43.7%) with 5.4 mg/kg and 40.0% (90%CI 33.1% to 47.6%) with 6.4 mg/kg. Among 808 patients in the exposure-safety analyses, the model-predicted estimates for the rates of any-grade interstitial lung disease (ILD) over a period of 180 days were 10.2% (90%CI 8.7% to 12.8%) with 6.4 mg/kg in gastric cancer and 9.7% (90%CI 8.2% to 11.8%) with 5.4 mg/kg in breast cancer. In gastric cancer, the efficacy of T-DXd was higher at 6.4 mg/kg than at 5.4 mg/kg. Exposure and ILD rates were comparable between 6.4 mg/kg in gastric cancer and 5.4 mg/kg in breast cancer. This study identified T-DXd 6.4 mg/kg as the recommended dose in HER2-positive gastric cancer.

Use of Real-World Evidence in a Virtual Bridging Analysis for a Human Epidermal Growth Factor Receptor 2-Targeted Antibody-Drug Conjugate in Gastric Cancer.

This study bridged pharmacokinetic, efficacy, and safety clinical trial data from Japan to a Western population using real-world evidence (RWE) to investigate the antibody-drug conjugate trastuzumab deruxtecan (T-DXd) in the treatment of human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer. Using population pharmacokinetic and exposure-response (efficacy/safety) models, exposure-efficacy data from 117 patients and exposure-safety data from 158 patients in Japan who received T-DXd 6.4 mg/kg as second-line or later treatment were bridged to RWE including covariate information from 25 Western patients with HER2-positive gastric cancer who received second-line or later T-DXd treatment. Pharmacokinetic simulations indicated that intact T-DXd and released drug (DXd) steady-state exposures were comparable between Western patients and patients from Japan; the Western/Japan ratio of exposure medians ranged from 0.82 (T-DXd steady-state minimum concentration) to 1.18 (DXd steady-state maximum concentration). Exposure-efficacy simulations estimated a confirmed objective response rate of 28.6% (90% confidence interval, 20.8-38.4) in real-world Western patients versus 40.1% (90% confidence interval, 33.5-47.0) in patients from Japan, possibly because of checkpoint inhibitor use in 4% versus 30% of patients, respectively. Western patients had a higher estimated rate of serious adverse events than patients from Japan (42.2% vs 34.6%); however, the rate of interstitial lung disease was lower (less than 10%) in Western patients. Overall, T-DXd was predicted to have meaningful clinical activity and a manageable safety profile in Western patients with HER2-positive gastric cancer. Using RWE, bridging analysis supported US approval of T-DXd 6.4 mg/kg in advanced gastric cancer before a clinical trial was completed in Western patients.

Exposure-Response Relationships in Patients With HER2-Positive Metastatic Breast Cancer and Other Solid Tumors Treated With Trastuzumab Deruxtecan.

Trastuzumab deruxtecan (T-DXd) is a HER2-targeting antibody-drug conjugate composed of a novel enzyme-cleavable linker and membrane-permeable topoisomerase I inhibitor payload. T-DXd has been approved for HER2-positive metastatic breast cancer and for HER2-positive metastatic gastric cancer. The approval in breast cancer was based on results from the DESTINY-Breast01 (U201; NCT03248492) and J101 (NCT02564900) trials. Here, we present dose justification for the approved 5.4 mg/kg every-3-weeks (Q3W) dose based on exposure-efficacy evaluated in patients with HER2-positive breast cancer (N = 337) from these 2 trials. Exposure-safety was assessed in patients with all tumor types (N = 639, n = 512 with breast cancer) across 5 trials, including J101 and DESTINY-Breast01. T-DXd doses ranged from 0.8-8.0 mg/kg Q3W; most patients received 5.4 (n = 312) or 6.4 mg/kg (n = 291). For each end point, multivariate logistic or Cox regression analysis was performed using various exposure metrics of T-DXd and released drug. A statistically significant association was observed between intact T-DXd area under the concentration-time curve (AUC) and confirmed objective response rate (ORR; P = 0.028). No significant exposure-response relationships were observed between intact T-DXd or released drug and duration of response or progression-free survival; however, follow-up was limited. All evaluated safety end points demonstrated a significant (P < 0.05) relationship with either intact T-DXd or released drug, with higher adverse event (AE) rates projected at higher exposures. Dose-response projections suggested an increase in ORR (67.5% vs. 62.9%) and toxicity (e.g., grade ≥ 3 all-cause treatment-emergent AEs: 61% vs. 54%) with T-DXd 6.4 vs. 5.4 mg/kg. Results demonstrate the benefit-risk profile at different doses and guide clinicians in the use of the 5.4-mg/kg Q3W dose in patients with HER2-positive metastatic breast cancer.

Population Pharmacokinetics of Trastuzumab Deruxtecan in Patients With HER2-Positive Breast Cancer and Other Solid Tumors.

Trastuzumab deruxtecan (DS-8201) is a human epidermal growth factor receptor 2 (HER2)-targeting antibody-drug conjugate with a novel enzyme-cleavable linker, a topoisomerase I inhibitor payload, and a drug-to-antibody ratio of ≈ 8. We have characterized the population pharmacokinetics (PK) of trastuzumab deruxtecan and released drug (topoisomerase I inhibitor) in patients with HER2-positive breast cancer or other solid tumor malignancies. This analysis includes pooled data from five clinical studies with 639 patients. Trastuzumab deruxtecan doses ranged from 0.8 to 8.0 mg/kg every 3 weeks. Serum concentrations of trastuzumab deruxtecan and released drug were analyzed using a sequential two-step approach, with the nonlinear mixed-effects modeling methods. Covariate assessment was based upon stepwise forward-addition and backward-elimination process, followed by both univariate and multivariate analysis quantifying their impact on steady-state exposure of trastuzumab deruxtecan and released drug. A two-compartment model with linear elimination best described PK profiles of intact trastuzumab deruxtecan, while a one-compartment model with time-varying release-rate constant and linear elimination described released-drug PK profiles. Statistically significant covariates (country, tumor size, sex, formulation, age, body weight, albumin, total bilirubin, and aspartate aminotransferase) resulted in < 20% change in steady-state area under the concentration-time curve of trastuzumab deruxtecan and released drug, except for increased body weight (95th percentile, 86 kg) and decreased albumin (5th percentile, 31 g/L). Analysis of patients stratified by country, race, renal function, and hepatic function found no clinically meaningful differences in steady-state exposure of intact trastuzumab deruxtecan or released drug. Overall, results suggest that no dose adjustment based on tested covariates or in specific patient populations is warranted.

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.

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.

Further Studies to Support the Use of Coproporphyrin I and III as Novel Clinical Biomarkers for Evaluating the Potential for Organic Anion Transporting Polypeptide 1B1 and OATP1B3 Inhibition.

In a recent study, limited to South Asian Indian subjects (n = 12), coproporphyrin (CP) I and CPIII demonstrated properties appropriate for an organic anion-transporting polypeptide (OATP) 1B endogenous probe. The current studies were conducted in healthy volunteers of mixed ethnicities, including black, white, and Hispanic subjects, to better understand the utility of these biomarkers in broader populations. After oral administration with 600 mg rifampin, AUC(0-24h) values were 2.8-, 3.7-, and 3.6-fold higher than predose levels for CPI and 2.6-, 3.1-, and 2.4-fold higher for CPIII, for the three populations, respectively. These changes in response to rifampin were consistent with previous results. The sensitivity toward OATP1B inhibition was also investigated by evaluating changes of plasma CP levels in the presence of diltiazem and itraconazole [administered as part of an unrelated drug-drug interaction (DDI) investigation], two compounds that were predicted to have minimal inhibitory effect on OATP1B. Administration of diltiazem and itraconazole did not increase plasma CPI and CPIII concentrations relative to prestudy levels, in agreement with predictions from in vitro parameters. Additionally, the basal CP concentrations in subjects with SLCO1B1 c.521TT genotype were comparable to those with SLCO1B1 c.521TC genotype, similar to studies with probe substrates. However, subjects with SLCO1B1 c.388AG and c.388GG genotypes (i.e., increased OATP1B1 transport activity for certain substrates) had lower concentrations of CPI than those with SLCO1B1 c.388AA. Collectively, these findings provide further evidence supporting the translational value of CPI and CPIII as suitable endogenous clinical probes to gauge OATP1B activity and potential for OATP1B-mediated DDIs.

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.

Daclatasvir: A Review of Preclinical and Clinical Pharmacokinetics.

Daclatasvir is a first-in-class, highly selective, hepatitis C virus, non-structural protein 5a polymerase replication complex inhibitor with picomolar potency and broad genotypic coverage in vitro. Daclatasvir undergoes rapid absorption, with a time to reach maximum plasma concentration of 1-2 h and an elimination half-life of ~ 10 to 14 h observed in single-ascending dose studies. Steady state was achieved by day 4 in multiple-ascending dose studies. Daclatasvir can be administered without regard to food or pH modifiers. Daclatasvir exposure is similar between healthy subjects and subjects infected with hepatitis C virus. Intrinsic factors such as age, race, or sex do not impact daclatasvir exposure. No dose adjustment is necessary for patients with any degree of hepatic or renal impairment. Daclatasvir has low-to-moderate clearance with the predominant route of elimination via cytochrome P450 3A4-mediated metabolism and P-glycoprotein excretion and intestinal secretion. Renal clearance is a minor route of elimination for daclatasvir. As a result, the dose of daclatasvir should be reduced from 60 to 30 mg once daily when co-administered with strong inhibitors of cytochrome P450 3A4. No dose adjustment is required when daclatasvir is co-administered with moderate inhibitors of cytochrome P450 3A4. The dose of daclatasvir should be increased from 60 to 90 mg once daily when co-administered with moderate inducers of cytochrome P450 3A4. Co-administration of daclatasvir with strong inducers of cytochrome P450 3A4 is contraindicated. Concurrent medications with inhibitory effects on P-glycoprotein without concurrent inhibition of cytochrome P450 3A4 are unlikely to cause marked changes in daclatasvir exposure, as the clearance of daclatasvir is through both cytochrome P450 3A4 and P-glycoprotein. The potential for daclatasvir to affect the pharmacokinetics of concomitantly administered drugs that are substrates of the cytochrome P450 enzyme system is low. In vitro, daclatasvir is a weak-to-moderate inhibitor of transporters including organic cation transporter 1, P-glycoprotein, organic transporting polypeptide 1B1, organic transporting polypeptide 1B3, and breast cancer resistance protein, although in clinical studies, daclatasvir has not altered the pharmacokinetics of concomitantly administered drugs that are substrates of these transporters to an appreciable degree, except for rosuvastatin. In summary, daclatasvir is a hepatitis C virus, non-structural protein 5a-selective inhibitor with a well-characterized pharmacokinetic profile that forms part of potent and well-tolerated all-oral treatment regimens for chronic hepatitis C virus infection.

Effects of a Fixed-Dose Co-Formulation of Daclatasvir, Asunaprevir, and Beclabuvir on the Pharmacokinetics of a Cocktail of Cytochrome P450 and Drug Transporter Substrates in Healthy Subjects.

BACKGROUND: A fixed-dose combination of daclatasvir (DCV; hepatitis C virus NS5A inhibitor), asunaprevir (ASV; non-structural protein 3 inhibitor), and beclabuvir (BCV; non-structural protein 5B inhibitor) is approved in Japan for hepatitis C virus genotype 1. OBJECTIVE: The objective of this study was to assess the combination's drug-drug interaction potential in vivo using a validated cocktail of eight cytochrome P450 (CYP) and transporter probes. METHODS: We conducted an open-label single-sequence study in healthy adults (n = 20) given single-dose caffeine (CYP1A2 substrate), metoprolol (CYP2D6), flurbiprofen (CYP2C9), montelukast (CYP2C8), omeprazole (CYP2C19), midazolam (CYP3A4), digoxin (P-glycoprotein), and pravastatin (organic anion-transporting polypeptide), alone or with steady-state twice-daily DCV/ASV/BCV 30/200/75 mg (with or without additional BCV 75 mg to adjust for higher exposure in hepatitis C virus infection). RESULTS: Daclatasvir/asunaprevir/beclabuvir did not affect CYP1A2, CYP2C8, or CYP2C9; the probe maximum observed concentration and area under the concentration-time curve extrapolated to infinite time geometric mean ratios and 90% confidence intervals were all within the 0.8-1.25 bioequivalence range. Beclabuvir showed moderate dose-dependent CYP2C19 induction; omeprazole maximum observed concentration and area under the concentration-time curve from 0 to the last quantifiable concentration were lower with additional BCV [geometric mean ratio 0.36 (90% confidence interval 0.23-0.55) and 0.34 (0.25-0.46), respectively] than without [0.57 (0.42-0.78), 0.48 (0.39-0.59)]. Weak-to-moderate CYP3A4 induction was observed, plus weak CYP2D6, P-glycoprotein, and organic anion-transporting polypeptide inhibition [maximum observed concentration and area under the concentration-time curve extrapolated to infinite time without additional BCV: midazolam 0.57 (0.50-0.65), 0.53 (0.47-0.60); metoprolol 1.40 (1.20-1.64), 1.71 (1.49-1.97); digoxin 1.23 (1.12-1.35), 1.23 (1.17-1.29); pravastatin 2.01 (1.63-2.47), 1.68 (1.43-1.97)]. CONCLUSIONS: No dose adjustments with DCV/ASV/BCV are indicated for CYP1A2, CYP2C8, CYP2C9, or P-glycoprotein substrates. CYP3A4, CYP2D6, and OATP substrates should be co-administered with caution. Co-administration with agents solely metabolized by CYP2C19 is not recommended.

Asunaprevir: An HCV Protease Inhibitor With Preferential Liver Distribution.

Asunaprevir is an inhibitor of the hepatitis C virus (HCV) NS3/4A protease, demonstrating efficacy in clinical studies in patients infected with HCV genotype 1 or 4, with either peginterferon/ribavirin or combinations of direct-acting antivirals. Because of preferential distribution of asunaprevir to the liver via organic anion-transporting polypeptide (OATP)-mediated transport, asunaprevir demonstrates high apparent oral clearance and very low plasma concentrations. Asunaprevir plasma concentrations are markedly increased by single-dose rifampin (an OATP inhibitor) and in subjects with moderate to severe hepatic impairment. In addition, modestly higher plasma concentrations of asunaprevir have been noted in subjects infected with HCV relative to healthy subjects and in Asian subjects relative to whites. At the marketed dose, infrequent hepatic transaminase abnormalities were poorly predicted by plasma concentrations. For a compound with these characteristics, hepatic concentrations may have provided an improved understanding of the in vivo pharmacokinetic and pharmacodynamic data to support decision making during development.

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.

A Review of Daclatasvir Drug-Drug Interactions.

The treatment of hepatitis C virus (HCV) infection has been revolutionized in recent years by the development of direct-acting antiviral regimens that do not contain peginterferon (pegIFN) and/or ribavirin (RBV). While direct-acting antiviral-based regimens have been shown to be greatly superior to pegIFN/RBV-based regimens in terms of efficacy and safety, they have a greater susceptibility to drug-drug interactions (DDIs). Daclatasvir (DCV)-the benchmark pangenotypic nonstructural protein 5A inhibitor-has been shown to be efficacious and generally well tolerated in partnership with other HCV direct-acting antivirals, including sofosbuvir, asunaprevir (ASV), and ASV plus beclabuvir. DCV may be the object of a DDI via the induction or inhibition of cytochrome P450 (CYP) 3A4 and/or P-glycoprotein (P-gp) by the concomitant medication, or the precipitant of a DDI via DCV-based induction/inhibition of CYP 3A4 or inhibition of P-gp, organic anion transporting polypeptide 1B1/B3, and/or breast cancer resistance protein. This article presents an overview of the drug interaction studies conducted during the clinical development of DCV, the findings of these studies that led to the guidance on concomitant medication use and dosage along with any required DCV dose modifications, and the use of the known metabolic pathway of DCV to guide concomitant dosing where direct drug-drug studies have not been conducted. The robust characterization of the DCV clinical pharmacology program has demonstrated that DCV has few or no clinically relevant DDIs with medications with which it is likely to be co-administered, and the majority of DDIs that do occur can be predicted and easily managed. FUNDING: Bristol-Myers Squibb.

A phase 3, open-label study of daclatasvir plus asunaprevir in Asian patients with chronic hepatitis C virus genotype 1b infection who are ineligible for or intolerant to interferon alfa therapies with or without ribavirin.

BACKGROUND AND AIM: Daclatasvir plus asunaprevir has demonstrated efficacy and safety in patients with chronic hepatitis C virus genotype 1b infection. This study focused on evaluating daclatasvir plus asunaprevir in interferon (±ribavirin)-ineligible or -intolerant Asian patients with genotype 1b infection from mainland China, Korea, and Taiwan. METHODS: Interferon (±ribavirin)-ineligible and -intolerant patients with genotype 1b infection received daclatasvir 60 mg tablets once daily plus asunaprevir 100 mg soft capsules twice daily for 24 weeks. The primary endpoint was sustained virologic response at post-treatment week 24 (SVR24). RESULTS: Of the 159 patients treated, 89.3% were Chinese, 65.4% were female, and 73.6% were interferon-intolerant. Cirrhosis was present in 32.7% of patients, and 40.3% had IL28B non-CC genotypes. SVR24 was achieved by 145/159 (91.2%) patients (100% concordance with SVR12) and was similarly high in cirrhotic patients (47/52, 90.4%). SVR24 was higher in patients without baseline NS5A (L31M or Y93H) resistance-associated variants (RAVs) (137/139, 98.6%), including those with cirrhosis (43/44, 97.7%). Prevalence of baseline NS5A RAVs was low (19/159, 11.9%), particularly in mainland China (10/127, 7.9%). One death (0.6%), five serious adverse events (3.1%), and three grade 4 laboratory abnormalities (1.9%) occurred on treatment; none were considered related to study drugs. Two patients (1.3%) discontinued because of adverse events. Treatment was generally well tolerated regardless of cirrhosis status. CONCLUSIONS: Daclatasvir plus asunaprevir achieved a SVR24 rate of 91.2%, rising to 98.6% in patients without baseline NS5A RAVs, and was generally well tolerated in interferon (±ribavirin)-ineligible or -intolerant patients with genotype 1b infection from mainland China, Korea, and Taiwan.

A highly sensitive and selective LC-MS/MS method to quantify asunaprevir, an HCV NS3 protease inhibitor, in human plasma in support of pharmacokinetic studies.

Asunaprevir (BMS-650032) is a selective hepatitis C virus (HCV) NS3 protease inhibitor with potent activity against HCV genotypes 1, 4, 5 and 6. It has been developed in conjunction with direct-acting antiviral agents, in interferon- and ribavirin-free regimen, to improve existing therapies for HCV infection. To support the pharmacokinetic analyses in asunaprevir clinical studies, we have developed and validated a highly sensitive and robust LC-MS/MS method to quantify asunaprevir in human EDTA plasma with an LLOQ of 0.05ng/mL, which was a 20-fold sensitivity improvement over a previously reported assay for asunaprevir. A deuterated labeled [D9]-asunaprevir was used as the internal standard (IS). The analyte and the IS were extracted using a semi-automated liquid-liquid extraction (LLE) at pH 7 with methyl-t-butyl ether (MTBE) in a 96-well plate containing 10µL of 10% CHAPS as the surfactant to prevent non-specific binding issue. Chromatographic separation was achieved on a Genesis C8 column (2.1×50mm, 4µm) with a gradient elution using 0.1% formic acid in water as mobile phase A and a mixture of methanol: acetone: formic acid (95:5:0.1; v/v/v) as the mobile phase B. Positive electrospray ionization was performed using multiple reaction monitoring (MRM) with transitions of m/z 748→648 for asunaprevir and m/z 757→649 for [D9]-asunaprevir,and a collision energy of 30 electron Volts (eV). The assay was validated over a standard curve range from 0.05 to 50ng/mL for asunaprevir in human plasma. The intra- and inter assay precisions were within 7.1% CV, and the % deviation was within 5.5% of their nominal concentrations. This assay has been successfully applied to multiple clinical studies with excellent assay ruggedness and reproducibility.

Asunaprevir: A Review of Preclinical and Clinical Pharmacokinetics and Drug-Drug Interactions.

Asunaprevir is a tripeptidic acylsulfonamide inhibitor of the hepatitis C virus (HCV) NS3/4A protease. Asunaprevir undergoes rapid absorption, with a time to reach maximum plasma concentration (T max) of 2-4 h and an elimination half-life (t ½) of ≈15-20 h observed in single-ascending dose studies. Steady state was achieved by day 7 in multiple-ascending dose studies. The large food effect observed with earlier formulations was mitigated by the soft-gel capsule. Asunaprevir demonstrates high apparent oral clearance and minimal renal elimination, and is eliminated primarily via cytochrome P450 (CYP) 3A4-mediated hepatic oxidative metabolism and faecal excretion. Highly preferential distribution of asunaprevir to the liver occurs via organic anion-transporting polypeptide (OATP)-mediated transport and results in low plasma concentrations. The condition of the liver affects disposition, as higher asunaprevir plasma exposures are observed in patients infected with HCV and/or hepatic impairment. Japanese patients also have higher exposure relative to North American/European patients, but comparable safety at the registrational dose. Asunaprevir has a low potential to perpetrate drug-drug interactions via CYP3A4, P-glycoprotein and OATP, but is a moderate CYP2D6 inhibitor; concomitant drugs that are substrates of CYP2D6 or P-glycoprotein and have a narrow therapeutic index should be used with care. Asunaprevir plasma exposure is strongly affected by inhibitors of OATP transport. No clinically significant interactions were observed between asunaprevir and daclatasvir or daclatasvir/beclabuvir. Asunaprevir has a complex pharmacokinetic profile and forms part of potent and well-tolerated all-oral regimens for the treatment of chronic HCV infection.

Single-dose pharmacokinetics and safety of daclatasvir in subjects with renal function impairment.

BACKGROUND: Daclatasvir (DCV) is a pangenotypic inhibitor of the HCV NS5A replication complex approved in Japan and Europe for combination treatment of HCV. AI444-063 was an open-label, two-stage, adaptive study assessing DCV pharmacokinetics and safety in HCV-uninfected subjects with renal impairment. METHODS: Stage 1 included 12 subjects with end-stage renal disease (ESRD) on dialysis and 12 healthy controls (creatinine clearance [CLcr]≥90 ml/min, Cockcroft-Gault) matched by sex, age and weight. All participants received a single DCV 60-mg dose on day 1. DCV plasma levels were measured through day 4. Prespecified criteria for study expansion (ESRD versus control area under the curve extrapolated to infinite time [AUC∞] geometric mean ratio [GMR] upper 90% CI>1.5) were met; therefore, 12 subjects with moderate or severe renal impairment (estimated glomerular filtration rate, 30-59 and 15-29 ml/min/1.73m(2), respectively) were included in stage 2. RESULTS: All 36 participants (30 male, mean age 54 years) completed the study. DCV AUC∞ was higher in ESRD subjects versus controls (GMR 1.264, 90% CI 0.989, 1.616). Compared with normal CLcr (90 ml/min), GMR and 90% CI for unbound DCV AUC∞ at CLcr 60, 30 and 15 ml/min were 1.18 (1.07, 1.30), 1.39 (1.14, 1.70) and 1.51 (1.18, 1.94), respectively. DCV was generally well tolerated in subjects with normal renal function, ESRD, or moderate or severe renal impairment. CONCLUSIONS: Observed DCV exposure increases were within the normal range of variability and were not associated with an elevated risk of adverse events. DCV can be administered in subjects with renal impairment, including ESRD, without dose modification. ClinicalTrials.gov NCT01830205.

Evaluation of drug-drug interaction between daclatasvir and methadone or buprenorphine/naloxone.

INTRODUCTION: Daclatasvir (DCV) is a potent hepatitis C virus (HCV) NS5A replication complex inhibitor with pangenotypic (1-6) activity in vitro. Methadone (MET) and buprenorphine (BUP) are opioid medications used to treat opioid addiction; patients on HCV therapy may require MET or BUP treatment. The effect of DCV on the pharmacokinetics (PK) of MET or BUP/naloxone (NLX) was assessed in subjects on stable MET or BUP. MATERIALS AND METHODS: An open-label, two-part study assessed the effect of steady-state oral administration of DCV on the PK of MET (Part 1, P1) or BUP/NAL (Part 2, P2). Safety/tolerability and pharmacodynamics (PD, opioid withdrawal scales/overdose assessment) were also assessed. Subjects (P1, N=14; P2, N=11) received daily single-dose oral MET (40-120mg) or BUP/NLX (8/2-24/6mg) based on their prescribed stable dose throughout, in addition to DCV (60mg QD) on Days 2-9. Serial PK sampling occurred predose and postdose till 24 hours on Day 1 (MET/BUP) and Day 10 (MET/BUP/DCV). Noncompartmental PK were derived. Geometric mean ratios (GMR) and 90% confidence intervals (90% CI) for MET/BUP/norBUP Cmax and AUCTAU were derived from linear mixed effects models. RESULTS: Subjects were aged 19-39 years, mostly white (P1, 93%; P2, 100%) and male (P1, 71%; P2, 91%). All subjects completed the study. No clinically meaningful effect was demonstrated as the GMR and 90% CIs fell within the prespecified interval (P1, 0.7-1.4; P2, 0.5-2.0: see Table 1). DCV coadministration was well-tolerated: overall, six (43%) subjects had adverse events (AEs) (all mild and resolved without treatment). DCV had no clinically significant effect on the PD of MET or BUP/NLX. CONCLUSIONS: Steady-state administration of DCV 60mg QD had no clinically meaningful effect on the PK of MET or BUP/NLX and was generally well-tolerated, suggesting that no dose adjustments will be required.