Abstract | BACKGROUND AND OBJECTIVES: 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.
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Authors | Akshanth R Polepally, Sven Mensing, Amit Khatri, Denise Beck, Wei Liu, Walid M Awni, Rajeev M Menon, Sandeep Dutta |
Journal | Clinical pharmacokinetics
(Clin Pharmacokinet)
Vol. 55
Issue 9
Pg. 1091-101
(09 2016)
ISSN: 1179-1926 [Electronic] Switzerland |
PMID | 27000758
(Publication Type: Clinical Trial, Phase I, Journal Article)
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Chemical References |
- Antiviral Agents
- Cyclopropanes
- Lactams, Macrocyclic
- Macrocyclic Compounds
- Protease Inhibitors
- Sulfonamides
- Ribavirin
- Proline
- Ritonavir
- paritaprevir
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Topics |
- Adolescent
- Adult
- Antiviral Agents
(administration & dosage, blood, pharmacokinetics)
- Biological Availability
- Cyclopropanes
- Drug Compounding
(methods)
- Drug Interactions
- Drug Therapy, Combination
- Female
- Healthy Volunteers
- Hepacivirus
(genetics)
- Hepatitis C
(drug therapy)
- Humans
- Lactams, Macrocyclic
- Macrocyclic Compounds
(administration & dosage, blood, pharmacokinetics, therapeutic use)
- Male
- Middle Aged
- Models, Biological
- Proline
(analogs & derivatives)
- Protease Inhibitors
(therapeutic use)
- Ribavirin
- Ritonavir
(administration & dosage, pharmacokinetics, therapeutic use)
- Sulfonamides
- Young Adult
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