Population Pharmacokinetics and Pharmacodynamics of Ribavirin in Patients with Chronic Hepatitis C Genotype 1 Infection

Jin, Runyan; Fossler, Michael J.; McHutchison, John G.; Howell, Charles D.; Dowling, Thomas C.

doi:10.1208/s12248-012-9368-z

Cited by 17 publications

(19 citation statements)

References 33 publications

(37 reference statements)

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“…Other estimated population parameters for ribavirin from our assessment were also in good agreement with published results in patients with chronic HCV genotype 1 infection (27). A notable difference between the previous population pharmacokinetic model and our findings was a 50% greater Vp/F for black versus white patients in the previous study (27). No such relationship was observed in our dataset.…”

Section: Discussionsupporting

confidence: 91%

“…Hence, no dose adjustment is necessary when ribavirin is given with the 3D regimen. The estimated CL/F and calculated apparent steady-state volume of distribution and t 1/2,z are in close agreement with the values reported in the literature (26,27). Other estimated population parameters for ribavirin from our assessment were also in good agreement with published results in patients with chronic HCV genotype 1 infection (27).…”

Section: Discussionsupporting

confidence: 90%

“…The estimated CL/F and calculated apparent steady-state volume of distribution and t 1/2,z are in close agreement with the values reported in the literature (26,27). Other estimated population parameters for ribavirin from our assessment were also in good agreement with published results in patients with chronic HCV genotype 1 infection (27). A notable difference between the previous population pharmacokinetic model and our findings was a 50% greater Vp/F for black versus white patients in the previous study (27).…”

Section: Discussionsupporting

confidence: 90%

“…Demographic distribution may account for some of the differences between studies; for example, the analyses by Jin and colleagues (27) included only 39 females (27% of their study population), whereas the present evaluation included 287 female patients. Jin and colleagues (27) did not assess CrCL because 85% of the participants had normal renal function, and decrements were generally mild in those outside the reference range. Our finding of an influence of CrCL is not unexpected, given the known effect of renal impairment on the pharmacokinetics of ribavirin, a renally cleared compound (28)(29)(30).…”

Section: Discussionmentioning

confidence: 73%

“…In our evaluation, sex and BWT were covariates for volume parameters, and sex and baseline CrCL for CL/F. Demographic distribution may account for some of the differences between studies; for example, the analyses by Jin and colleagues (27) included only 39 females (27% of their study population), whereas the present evaluation included 287 female patients. Jin and colleagues (27) did not assess CrCL because 85% of the participants had normal renal function, and decrements were generally mild in those outside the reference range.…”

Section: Discussionmentioning

confidence: 84%

See 4 more Smart Citations

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

Mensing

Polepally

König

et al. 2015

AAPS J

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Abstract. 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.

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Section: Discussionsupporting

confidence: 91%