Industry Perspective on Standardizing Food-Effect Studies for New Drug Development.

Investigating the effect of food on bioavailability during the development of an oral drug product is of prime importance because it has major implications on the study design of the clinical trials and dosing and administration recommendations. For modified-release formulations that exhibit dose dumping when administered with food, this may result in clinical concerns around safety and efficacy. In this article, we provide an overview of the various considerations in our opinion that impact the design and conduct of food-effect studies. We summarize the various recommendations from the different regulatory agencies and provide specific suggestions on study conduct in terms of statistical design, timing of studies, subject selection, and type and caloric content of the meal. We also discuss the role of modeling and simulation. Finally, we present an interpretation of the results of food-effect studies in addition to dosing and labeling recommendations in relation to regulatory guidance documents.

Methotrexate Dose in Patients With Early Rheumatoid Arthritis Impacts Methotrexate Polyglutamate Pharmacokinetics, Adalimumab Pharmacokinetics, and Efficacy: Pharmacokinetic and Exposure-response Analysis of the CONCERTO Trial.

PURPOSE: Methotrexate (MTX) and adalimumab are well-recognized treatments of rheumatoid arthritis (RA), the efficacy of which may be driven by intracellular polyglutamates (PGs). The aim of this analysis was to characterize MTX PG concentrations and adalimumab pharmacokinetics in the CONCERTO trial. In addition, the relationships between MTX dose/pharmacokinetics, adalimumab pharmacokinetics, and efficacy were evaluated. METHODS: CONCERTO was a double-blind, parallel-arm study in patients with early RA randomized to adalimumab 40 mg SC every other week plus blinded MTX 2.5, 5, 10, or 20 mg PO once weekly, for 26 weeks. Blood samples were obtained through week 26 for the determination of concentrations of MTX PG, adalimumab, and anti-adalimumab antibody (AAA). Clinical outcomes were also assessed. FINDINGS: A total of 395 patients were included in the analysis (MTX, 329; adalimumab, 395). The mean time to steady-state MTX PG concentration was increased with MTX dose, from 8 to >26 weeks, depending on PG chain length. Dose proportionality changed with PG chain length. As MTX dose was increased, the percentage of short-chain PGs increased less than dose proportionally, while the percentage of long-chain PGs increased more than dose proportionally. For very-long-chain PGs, dose proportionality could not be assessed due to the nonmeasurable concentrations in the 2.5- and 5-mg MTX dose groups. As MTX dose increased, mean adalimumab concentrations also increased (P < 0.001). The percentage of patients with AAA decreased with increasing MTX dose, and at week 26, AAA+ status was significantly correlated with MTX dose level (P = 0.005). In general, rates of response, defined using the 28-joint count disease activity score based on C-reactive protein (DAS28[CRP]; response, <3.2), were greater in the subgroup without AAA. The likelihood of a patient achieving a DAS28(CRP) response was related to the baseline measurement (P < 0.001) and to the concentration of adalimumab (P = 0.001), but not to the MTX regimen (P = 0.689). IMPLICATIONS: The dose-response characteristics of MTX PG pharmacokinetics and the resultant effects of MTX on adalimumab exposures should be considered when determining the benefit-risk profile of MTX and adalimumab combination therapy in patients with early RA. ClinicalTrials.gov identifier: NCT01185301.

Relationship Between Atrasentan Concentrations and Urinary Albumin to Creatinine Ratio in Western and Japanese Patients With Diabetic Nephropathy.

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.

Application of Exposure-Response Analyses to Establish the Pharmacodynamic Similarity of a Once-Daily Regimen to an Approved Twice-Daily Dosing Regimen for the Treatment of HCV Infection.

The triple direct-acting antiviral (3-DAA) regimen (two co-formulated tablets of ombitasvir/paritaprevir/ritonavir once daily and one tablet of dasabuvir twice daily) for patients with hepatitis C virus (HCV) genotype 1 infection has been reformulated for once-daily administration containing all three active DAAs (3QD regimen). Two bioequivalence studies compared the 3-DAA and 3QD regimens. In study 1, fed, single-, and multiple-dose crossover comparisons revealed exposures for drug components that were slightly outside the bioequivalence criteria, i.e., 21 to 29% lower dasabuvir C trough, paritaprevir C max, and ritonavir C max. In study 2, fed and fasted single-dose crossover comparisons demonstrated a large impact of food on exposures, confirming the product's labeling requirement for administration only with food, and revealed a lack of bioequivalence under fasting conditions. Exposure-response analyses using efficacy data from phase 2/3 studies of the 3-DAA regimen demonstrated that the lower dasabuvir C trough for the 3QD regimen (under fed condition) would have minimal impact on sustained virologic response at week 12 post-treatment (SVR12). Thus, the pharmacodynamic similarity between the regimens was established and the analyses provided the basis for regulatory approval of the 3QD regimen to treat patients with chronic HCV genotype 1 infection.

Clinical Pharmacokinetics of Paritaprevir.

Paritaprevir is a potent hepatitis C virus (HCV) nonstructural (NS) protein 3/4A protease inhibitor that is used in combination with other direct-acting antivirals (DAAs) for the treatment of chronic HCV infection. Paritaprevir is primarily metabolized by cytochrome P450 (CYP) 3A4 and is administered with a low dose of ritonavir to achieve drug concentrations suitable for once-daily dosing. Coadministration of paritaprevir with ritonavir increases the half-life of single-dose paritaprevir from approximately 3 h to 5-8 h, doubles the time to maximum plasma concentration (T max) from 2.3 to 4.7 h, and increases exposures 30-fold for maximum observed plasma concentration (C max), 50-fold for area under the plasma concentration-time curve (AUC), and >300-fold for trough concentration (C 24). Paritaprevir displays highly variable, nonlinear pharmacokinetics, with C max and AUC increasing in a greater than dose proportional manner when administered with or without ritonavir. In the presence of ritonavir, paritaprevir is excreted mostly unchanged in feces via biliary excretion. Paritaprevir exposures are higher in Japanese subjects compared with Caucasian subjects; however, no dose adjustment is needed for Japanese patients as the higher exposures are safe and well tolerated. The pharmacokinetic characteristics of paritaprevir are similar between healthy subjects and HCV-infected patients, and are not appreciably altered by mild or moderate hepatic impairment or mild, moderate, or severe renal impairment, including those on dialysis. Paritaprevir exposures are increased in patients with severe hepatic impairment. Although the presence of a low dose of ritonavir in paritaprevir-containing regimens increases the likelihood of drug-drug interactions, results from several drug interaction studies demonstrated that paritaprevir-containing regimens can be coadministered with many comedications that are commonly prescribed in HCV-infected patients.

Pharmacokinetics and Tolerability of Anti-Hepatitis C Virus Treatment with Ombitasvir, Paritaprevir, Ritonavir, with or Without Dasabuvir, in Subjects with Renal Impairment.

BACKGROUND: The direct-acting antiviral agent (DAA) combination of ombitasvir and paritaprevir (administered with ritonavir) with (3D regimen) or without (2D regimen) dasabuvir has shown very high efficacy rates in the treatment of chronic hepatitis C virus (HCV) infection. Renal impairment, a common comorbidity in patients with chronic HCV infection, can influence the pharmacokinetics of antiviral agents and hence their efficacy and safety profiles. OBJECTIVE: The aim of this study was to evaluate the influence of renal impairment on the pharmacokinetics and tolerability of the 3D and 2D regimens. METHODS: Overall, 24 subjects, six in each of four renal function groups (normal, mild, moderate, and severe), received a single dose of the 3D and 2D regimens in separate dosing periods. Plasma and urine were analyzed to assess the effect of renal impairment on drug exposure. RESULTS: DAA exposures changed by up to 21, 37, and 50 % in subjects with mild, moderate, and severe renal impairment, respectively, versus subjects with normal renal function. Ritonavir exposure increased with the degree of renal impairment (maximum 114 %). The half-lives of DAAs and ritonavir in subjects with renal impairment were generally comparable with those in healthy subjects. No safety or tolerability concerns arose in this study. CONCLUSION: The 3D and 2D regimens do not require dose adjustment for patients with HCV infection and concomitant renal impairment.

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.

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.

Relationship between venetoclax exposure, rituximab coadministration, and progression-free survival in patients with relapsed or refractory chronic lymphocytic leukemia: demonstration of synergy.

Venetoclax is indicated at a dosage of 400 mg daily (QD) for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion who have received at least 1 prior therapy. Ongoing trials are evaluating venetoclax in combination with CD20 targeting monoclonal antibodies, such as rituximab. The objective of this research was to characterize the relationship between venetoclax exposures and progression-free survival (PFS) and to evaluate the effect of rituximab coadministration on PFS in patients with relapsed or refractory (R/R) CLL/small lymphocytic lymphoma (SLL). A total of 323 patients from 3 clinical studies of venetoclax, with and without rituximab coadministration, were pooled for the analyses. A time-variant relative risk survival model was used to relate plasma venetoclax concentrations and rituximab administration to PFS. Demographics and baseline disease characteristics were evaluated for their effect on PFS. A concentration-dependent effect of venetoclax on PFS and a prolonged synergistic effect of 6 cycles of concomitant rituximab were identified. The 17p deletion chromosomal aberration was not identified to affect the PFS of patients treated with venetoclax. A venetoclax dose of 400 mg daily QD was estimated to result in a substantial median PFS of 1.8 years (95% confidence interval [CI], 1.7-2.1), whereas the addition of 6 cycles of rituximab was estimated to increase the median PFS to 3.9 years (95% CI, 2.8-5.6). The analysis demonstrates a concentration-dependent effect of venetoclax on PFS and also a synergistic effect with rituximab. Combining venetoclax with the CD20 targeting monoclonal antibody rituximab in R/R CLL/SLL patients provides substantial synergistic benefit compared with increasing the venetoclax monotherapy dose.

Effect of co-medications on paritaprevir, ritonavir, ombitasvir, dasabuvir and ribavirin pharmacokinetics: analysis of data from seven Phase II/III trials.

BACKGROUND: The three drug direct-acting antiviral regimen (3D regimen) of ombitasvir, paritaprevir/ritonavir and dasabuvir, with and without ribavirin, was evaluated in one Phase II trial and six Phase III trials in over 2,300 HCV genotype-1-infected patients. Patients continued taking their protocol-permitted co-medications while receiving the 3D ± ribavirin regimen. The effects of the co-medications on exposures of the 3D regimen and ribavirin were examined. METHODS: Population pharmacokinetic model-predicted steady-state area under the curve (AUC24,ss) values were evaluated in the presence/absence of the co-medications. Interactions resulting in a greater than 50% reduction or 100% increase in an AUC24,ss value were examined as covariates for an effect on apparent clearance (CL/F). RESULTS: More than 1,200 co-medications belonging to 15 drug classes and/or 19 enzyme and transporter inhibitor and/or inducer categories were used concomitantly with the 3D regimen in the trials. Approximately 1,500 patients (65%) in Phase III trials received two or more co-medications from multiple drug classes or categories. No co-medication class/category decreased or increased ombitasvir, dasabuvir, ritonavir or ribavirin AUC24,ss by more than half or twofold, respectively. Opioids, antipsychotics, anti-epileptics, antidiabetics and non-ethinyl estradiol-containing hormone replacement therapies appeared to have an effect (AUC24,ss ratio ≤0.5 or ≥2.0) on paritaprevir exposures. However, when these classes were included in the paritaprevir population pharmacokinetic model, only opioids and antidiabetics had a statistically significant effect on CL/F, but with no clinically meaningful increase in exposures (≤55%). CONCLUSIONS: No dose adjustment is necessary for the 3D ± ribavirin regimen when used with the co-medications included in this analysis as there were no clinically meaningful effects on exposures of the DAAs.

Pharmacokinetics of Tacrolimus and Cyclosporine in Liver Transplant Recipients Receiving 3 Direct-Acting Antivirals as Treatment for Hepatitis C Infection.

BACKGROUND: Interactions between tacrolimus and cyclosporine (CSA) and the 3 direct-acting antiviral regimen (3D) of ombitasvir, paritaprevir/ritonavir, and dasabuvir necessitate a priori dose adjustments for the immunosuppressants to achieve desired levels. Modeling and simulations based on data in healthy subjects predicted that tacrolimus 0.5 mg every 7 days or 0.2 mg every 3 days, and CSA at one-fifth the total daily dose administered once daily, would achieve desired trough concentrations (Ctrough) during 3D treatment. The success of these dosing recommendations was evaluated by analyzing pharmacokinetic data from liver transplant recipients in the CORAL-I study. METHODS: A population pharmacokinetic model was developed using tacrolimus dosing and Ctrough data before and during 3D treatment (n = 29). The model was used to simulate various tacrolimus dosing regimens and predict tacrolimus concentration-time profiles during 3D treatment. CSA Ctrough data before and during 3D treatment (n = 5) were also summarized. RESULTS: A one-compartment model with first-order absorption adequately described tacrolimus pharmacokinetic profiles during the first 4 weeks of 3D treatment. Estimated tacrolimus Ctrough values (median; interquartile range) before and during 3D treatment were comparable (5.7 ng/mL; 4.9-6.5 ng/mL versus 5.2 ng/mL; 4.2-6.3 ng/mL, respectively). Based on simulations, in a patient with a starting Ctrough of 6 ng/mL, 0.5 mg tacrolimus every 7 or 14 days or 0.2 mg tacrolimus every 3 days will result in Ctrough levels of 6-9 ng/mL, 4-6 ng/mL, and 6-10 ng/mL, respectively, during 3D treatment. For CSA, Ctrough values (median; interquartile range) before and during 3D treatment were comparable (126 ng/mL; 94-140 ng/mL versus 104 ng/mL; 82-140 ng/mL). CONCLUSIONS: Observed data for tacrolimus and CSA in liver transplant recipients confirm that the recommended dosing strategies are valid and therapeutic levels of immunosuppression can be maintained during 3D treatment.

Drug-Drug Interaction of Omeprazole With the HCV Direct-Acting Antiviral Agents Paritaprevir/Ritonavir and Ombitasvir With and Without Dasabuvir.

Paritaprevir (administered with low-dose ritonavir), ombitasvir, and dasabuvir are direct-acting antiviral agents administered as combination regimens for the treatment of chronic hepatitis C virus infection. Drug-drug interactions between 2D (ombitasvir/paritaprevir/ritonavir) or 3D (ombitasvir/paritaprevir/ritonavir and dasabuvir) regimens and omeprazole, a CYP2C19 substrate and acid-reducing agent, were evaluated in 24 healthy volunteers. Subjects received omeprazole (40 mg once daily) on day 1 and days 20-24 and the 2D or 3D regimen (ombitasvir/paritaprevir/ritonavir 25/150/100 mg once daily ± dasabuvir 250 mg twice daily) on days 6-24. Compared with omeprazole alone, coadministration with the 2D or 3D regimen decreased omeprazole geometric mean Cmax and AUCt values by 40% to 50%. Ombitasvir, dasabuvir, and ritonavir mean exposures showed <10% change, and paritaprevir mean exposures showed <20% change when the 2D or 3D regimen was administered with omeprazole compared with administration without omeprazole. Although no a priori dose adjustment is needed, a higher omeprazole dose should be considered if clinically indicated when coadministered with the 2D or 3D regimen. No dose adjustment is required for the 2D or 3D regimen when administered with omeprazole, other acid-reducing agents, or CYP2C19 inhibitors.

Dose- and Formulation-Dependent Non-Linear Pharmacokinetic Model of Paritaprevir, a Protease Inhibitor for the Treatment of Hepatitis C Virus Infection: Combined Analysis from 12 Phase I Studies.

BACKGROUND AND OBJECTIVES: Paritaprevir is a direct-acting antiviral agent that is a component of approved multidrug regimens used in the treatment of hepatitis C virus (HCV) infection. A population pharmacokinetic model for paritaprevir was developed using data from formulation, bioavailability, and drug-drug interaction studies that evaluated the pharmacokinetics of paritaprevir (coadministered with ritonavir to enhance exposure) with or without ombitasvir and/or dasabuvir at different paritaprevir dose levels. METHODS: A non-linear mixed-effects modeling approach was applied to data from 12 phase I, single- and multiple-dose studies that enrolled a total of 369 healthy volunteers. Age, sex, race, ethnicity, body weight, body surface area, body mass index, and baseline creatinine clearance were evaluated as covariates during model development. In addition, the influences of dose, formulation, and concomitant medications (e.g. ombitasvir and dasabuvir) on paritaprevir bioavailability were included in the model. RESULTS: A two-compartment model with first-order absorption and elimination optimally described paritaprevir plasma concentration-time data. Paritaprevir bioavailability was formulation- and dose-dependent, and increased supraproportionally. The accumulation of paritaprevir was 1.57-fold on repeated dosing compared with the first dose. Coadministration of dasabuvir increased paritaprevir bioavailability by 59 %; however, ombitasvir coadministration did not affect the pharmacokinetic profile of paritaprevir. No subject-specific covariate influenced the paritaprevir pharmacokinetics. The pharmacokinetic model was robust in bootstrap evaluations and was consistent with observed data based on diagnostic goodness-of-fit plots and visual predictive checks. CONCLUSION: The complex pharmacokinetics of paritaprevir were well described by the model, which can be used as a basis for clinical trial dosing and further evaluations in patients with HCV.

Drug-Drug Interactions between Sofosbuvir and Ombitasvir-Paritaprevir-Ritonavir with or without Dasabuvir.

The combination of ombitasvir (an NS5A inhibitor), paritaprevir (an NS3/4A inhibitor) coadministered with ritonavir (r), and dasabuvir (an NS5B nonnucleoside polymerase inhibitor), referred to as the 3D regimen, and the combination of ombitasvir-paritaprevir-r, referred to as the 2D regimen, have demonstrated high efficacy with and without ribavirin in hepatitis C virus (HCV)-infected subjects. These regimens have potential for coadministration with sofosbuvir (nucleoside NS5B inhibitor) in the treatment of HCV. This phase 1, drug-drug interaction, open-label, multiple-dose study enrolled 32 healthy subjects to receive the 3D or 2D regimen in combination with sofosbuvir. Doses of study drugs were as follows: ombitasvir-paritaprevir-r, 25/150/100 mg daily (QD); dasabuvir, 250 mg twice daily (BID); and sofosbuvir, 400 mg QD. Blood samples were collected on study days 7, 14, and 21 for evaluating drug interaction at steady state. The effect of the 3D and 2D regimens on the pharmacokinetics of sofosbuvir and its circulating metabolite GS-331007 and vice versa was assessed by a repeated-measures analysis. Exposures of the 3D and 2D regimens were similar (≤20% change) during coadministration with sofosbuvir and during administration alone. Sofosbuvir exposures were 61% to 112% higher with the 3D regimen and 64% to 93% higher with the 2D regimen than with sofosbuvir alone. GS-331007 total exposures were 27% and 32% higher with the 3D and 2D regimens, respectively, than with sofosbuvir alone. Increases in sofosbuvir and GS-331007 exposures likely resulted from breast cancer resistance protein (BCRP) and/or P glycoprotein (P-gp) transporter inhibition by paritaprevir and ritonavir. No subjects discontinued the study due to study drug-related adverse events. No dose adjustment is recommended for 3D, 2D, or sofosbuvir in clinical trials exploring the safety and efficacy of the combination. (This study has been registered at ClinicalTrials.gov under registration no. NCT02356562 and NCT02292719.).

Population Pharmacokinetics of Paritaprevir, Ombitasvir, Dasabuvir, Ritonavir, and Ribavirin in Patients with Hepatitis C Virus Genotype 1 Infection: Combined Analysis from 9 Phase 1b/2 Studies.

Direct-acting antiviral agents (DAAs) are established as the standard of care for chronic hepatitis C virus (HCV) infection. One of the newest additions to the HCV arsenal is an oral three-DAA combination therapy (i.e., the 3D regimen) that does not require concomitant use of pegylated interferon. The clinical development program for the 3D regimen has yielded a robust dataset that is inclusive of various dosing schemes and a diverse patient population. Using data from nine phase 1b/2a/2b studies that enrolled patients with HCV genotype 1 infection, population pharmacokinetic models were developed for each component of the 3D regimen (ombitasvir, paritaprevir, ritonavir, and dasabuvir) and for ribavirin, an adjunctive therapy used to enhance therapeutic efficacy in some populations. Formulation effects, accumulation, relative bioavailability, and interactions between DAAs were assessed during model development, and demographic and clinical covariates were identified and evaluated for their effects on drug exposures. Proposed models were assessed via goodness-of-fit plots, visual predictive checks, and bootstrap evaluations. Population pharmacokinetic models adequately described their respective plasma concentration-time data with precise and reliable model parameter estimates and with good predictive performance. Covariates, including age, sex, body weight, cytochrome P450 2C8 inhibitor use, non-Hispanic ethnicity, and creatinine clearance, were associated with apparent clearance and/or apparent volume parameters; however, the magnitude of effect on drug exposure was modest and not considered to be clinically significant. No patient-related or clinical parameters were identified that would necessitate dose adjustment of the 3D regimen in patients with HCV genotype 1 infection.

Drug Interactions with the Direct-Acting Antiviral Combination of Ombitasvir and Paritaprevir-Ritonavir.

The two direct-acting antiviral (2D) regimen of ombitasvir and paritaprevir (administered with low-dose ritonavir) is being developed for treatment of genotype subtype 1b and genotypes 2 and 4 chronic hepatitis C virus (HCV) infection. Drug-drug interactions were evaluated in healthy volunteers to develop dosing recommendations for HCV-infected subjects. Mechanism-based interactions were evaluated for ketoconazole, pravastatin, rosuvastatin, digoxin, warfarin, and omeprazole. Interactions were also evaluated for duloxetine, escitalopram, methadone, and buprenorphine-naloxone. Ratios of geometric means with 90% confidence intervals for the maximum plasma concentration and the area under the plasma concentration-time curve were estimated to assess the magnitude of the interactions. For most medications, coadministration with the 2D regimen resulted in a <50% change in exposures. Ketoconazole, digoxin, pravastatin, and rosuvastatin exposures increased by up to 105%, 58%, 76%, and 161%, respectively, and omeprazole exposures decreased by approximately 50%. Clinically meaningful changes in ombitasvir, paritaprevir, or ritonavir exposures were not observed. In summary, all 11 medications evaluated can be coadministered with the 2D regimen, with most medications requiring no dose adjustment. Ketoconazole, digoxin, pravastatin, and rosuvastatin require lower doses, and omeprazole may require a higher dose. No dose adjustment is required for the 2D regimen.

Pharmacokinetics and safety of co-administered paritaprevir plus ritonavir, ombitasvir, and dasabuvir in hepatic impairment.

BACKGROUND & AIMS: Paritaprevir, ombitasvir, and dasabuvir are direct-acting antivirals for treatment of chronic hepatitis C virus (HCV) infection. The aim of this study was to characterize the effects of mild, moderate, and severe hepatic impairment on the pharmacokinetics of these drugs. METHODS: HCV-negative subjects with normal hepatic function (n=7) or mild (Child-Pugh A, n=6), moderate (Child-Pugh B, n=6), or severe (Child-Pugh C, n=5) hepatic impairment received a single-dose of the combination of paritaprevir plus ritonavir (paritaprevir/r, 200/100 mg), ombitasvir (25 mg), and dasabuvir (400 mg). Plasma samples were collected through 144 hours after administration for pharmacokinetic assessments. RESULTS: Paritaprevir, ombitasvir, dasabuvir, and ritonavir exposures (maximal plasma concentration, C(max), and area under the concentration-time curve, AUC) were minimally affected in subjects with mild or moderate hepatic impairment. Differences in exposures between healthy controls and subjects with mild or moderate hepatic impairment were less than 35%, except for 62% higher paritaprevir AUC in subjects with moderate hepatic impairment. Paritaprevir and dasabuvir AUC were significantly higher in subjects with severe hepatic impairment (950% and 325%, respectively). However, ombitasvir AUC was 54% lower and ritonavir AUC was comparable. Adverse events included eye stye, insomnia, and pain from an infiltrated intravenous line. CONCLUSIONS: The changes observed in paritaprevir, ritonavir, ombitasvir, and dasabuvir exposures in subjects with mild or moderate hepatic impairment do not necessitate dose adjustment. Subjects with severe hepatic impairment had substantially higher paritaprevir and dasabuvir 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.

Drug-drug interaction profile of the all-oral anti-hepatitis C virus regimen of paritaprevir/ritonavir, ombitasvir, and dasabuvir.

BACKGROUND & AIMS: Paritaprevir (administered with ritonavir, PTV/r), ombitasvir (OBV), and dasabuvir (DSV) are direct-acting antiviral agents (DAAs) for the treatment of chronic hepatitis C virus (HCV) infection. Thirteen studies were conducted to characterize drug-drug interactions for the 3D regimen of OBV, PTV/r, and DSV and various medications in healthy volunteers to inform dosing recommendations in HCV-infected patients. METHODS: Mechanism-based drug-drug interactions were evaluated for gemfibrozil, ketoconazole, carbamazepine, warfarin, omeprazole, digoxin, pravastatin, and rosuvastatin. Drug-drug interactions with medications commonly used in HCV-infected patients were evaluated for amlodipine, furosemide, alprazolam, zolpidem, duloxetine, escitalopram, methadone, buprenorphine/naloxone, and oral contraceptives. Ratios of geometric means with 90% confidence intervals for maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) were used to determine the magnitude of interaction. RESULTS: Coadministration with the 3D regimen of OBV, PTV/r, and DSV resulted in a <2-fold change in mean Cmax and AUC for most medications and the DAAs, indicating minimal to modest interactions. Carbamazepine decreased PTV, ritonavir, and DSV exposures substantially, while gemfibrozil increased DSV exposures substantially. Although coadministration with ethinyl estradiol-containing contraceptives resulted in elevated alanine aminotransferase levels, coadministration with a progestin-only contraceptive did not. CONCLUSIONS: The majority of medications can be coadministered with the 3D regimen of OBV, PTV/r, and DSV without dose adjustment, or with clinical monitoring or dose adjustment. Although no dose adjustment is necessary for the 3D regimen when coadministered with 17 of the 20 medications, coadministration with gemfibrozil, carbamazepine, or ethinyl estradiol-containing contraceptives is contraindicated.

Studying navitoclax, a targeted anticancer drug, in healthy volunteers--ethical considerations and risk/benefit assessments and management.

BACKGROUND: Biopharmaceutical studies for anti-cancer drugs are typically conducted in cancer patients due to unacceptable toxicities to healthy volunteers. Navitoclax is a first-in-class, orally bioavailable, targeted Bcl-2 family protein inhibitor that has been studied in cancer patients. METHODS: A strategy that integrated the evaluation of non-clinical toxicology data and clinical data in cancer patients was employed to assess the feasibility, determine doses and establish risk management plans for studying navitoclax in healthy volunteers. Two relative bioavailability/food effect studies with either a 25 mg dose or 50 and 100 mg doses of navitoclax were conducted sequentially in healthy female volunteers of non-childbearing potential. RESULTS/CONCLUSION: Navitoclax was well-tolerated in both studies in healthy volunteers, and did not impose risks beyond the minimal levels expected in healthy volunteer studies. Compared to a similar study in cancer patients, the studies in healthy volunteers generated higher quality data in a short period of time to support formulation selection.