Barbara J. Brennan

Physiological modeling and assessments of regional drug bioavailability of danoprevir to determine whether a controlled release formulation is feasible.

Danoprevir, a potent, selective inhibitor of HCV NS3/4A protease, has a short half‐life in humans. Therefore, the feasibility of a controlled release (CR) formulation to allow less frequent dosing was investigated using experimental approaches and physiological modeling to examine whether danoprevir is absorbed in the colon. Danoprevir absorption was studied in portal‐vein‐cannulated monkeys and in monkeys surgically modified to make intraduodenal, intrajejunal, intracolonic and oral administration possible. In portal‐vein‐cannulated monkeys, absorption was apparent up to 24 h after administration. The observed relative bioavailability from intracolonic delivery in the monkey was approximately 30% relative to oral administration, consistent with the model prediction of 40%. Human relative bioavailability for a tablet delivered to the colon compared with an immediate release (IR) formulation was predicted to be 4–28%. Preclinical data and modeling suggested that CR development would be challenging for this Biopharmaceutics Classification System Class IV compound. Therefore, a confirmative study in healthy volunteers was conducted to investigate the relative bioavailability of danoprevir in various regions of the gastrointestinal tract. In a randomized, open‐label, crossover study, subjects received 100 mg danoprevir IR soft gel capsule, 100 mg danoprevir solution delivered to the distal small bowel and colon via an Enterion™ capsule (a remotely activated capsule for regional drug delivery) and 100 mg danoprevir powder to the colon via an Enterion™ capsule. The relative bioavailability of danoprevir (compared with IR) delivered to the colon was 6.5% for a solution and 0.6% for a powder formulation, indicating that a CR formulation is not feasible. Copyright

Effect of peginterferon alfa-2a (40KD) on cytochrome P450 isoenzyme activity.

Pegylated interferon‐based therapy is recommended for treatment of hepatitis C virus (HCV) infection. Because interferons are known to down‐regulate hepatic cytochrome P450 (CYP) enzymes, which are involved in drug metabolism and clearance, there is a need to investigate the effect of peginterferon (PEG‐IFN) alfa‐2a (40KD) on the activity of these enzymes in vivo.

Evaluation of pharmacokinetics, user handling, and tolerability of peginterferon alfa-2a (40 kDa) delivered via a disposable autoinjector device.

Background Peginterferon alfa-2a (40 kDa) is currently administered using a prefilled syringe. The peginterferon alfa-2a disposable autoinjector is a new safety-engineered device designed to facilitate injection and reduce the risk of needlestick injuries. The analysis of two open-label Phase I trials evaluated the pharmacokinetics, successful administration, and tolerability of peginterferon alfa-2a when using the autoinjector. The studies were performed to support the filing and registration of the autoinjector device. Methods In trial 1, 50 healthy adult subjects received one 180 μg dose of peginterferon alfa-2a via the autoinjector. Serial blood samples were collected predose, up to 336 hours following drug administration, and at follow-up (28 ± 3 days post-dosing) for noncompartmental pharmacokinetic analysis. Trial 2 randomized 60 adult patients with chronic hepatitis C to 180 μg peginterferon alfa-2a once weekly by the autoinjector or prefilled syringe for 3 weeks followed by the alternative device (prefilled syringe or autoinjector, respectively) for 3 weeks. Patients also received ribavirin. Administration by the devices was evaluated under direct observation by a study staff member and by patient subjective assessment. Results In trial 1, following a single dose of peginterferon alfa-2a, the maximum plasma concentration was 16.1 ± 5.3 ng/mL (mean ± standard deviation), and area under the concentration time curve (0–168 hours) was 1996 ± 613 ng · hour/mL, similar to that reported using a vial/syringe or prefilled syringe. In trial 2, few patients showed handling difficulties with either device. Generally, patients were observed to be more satisfied and confident, followed instructions better, and successfully initiated injection with the autoinjector versus the prefilled syringe. Patients reported the autoinjector to be more convenient and easier to use. No pain or discomfort was experienced using the autoinjector. The autoinjector safety profile was consistent with that known for peginterferon alfa-2a/ribavirin. Conclusion These results indicate that peginterferon alfa-2a can be successfully and safely delivered via the autoinjector and that the device is easy to handle.

Effect of R667, a Novel Emphysema Agent, on the Pharmacokinetics of Midazolam in Healthy Men

The purpose of this study was to investigate the potential for a CYP3A4‐mediated drug interaction between R667 and midazolam (MDZ) in healthy subjects. R667 is metabolized by CYP3A4 and therefore may interact with CYP3A4 substrates. In the present study, 18 healthy male subjects received a single 15‐mg oral dose of MDZ with and without R667 coadministration. Serial blood samples were collected predose and up to 24 hours after each MDZ dose for pharmacokinetic (PK) evaluation. The PK parameters for MDZ, R667, and metabolites were estimated using noncompartmental methods. MDZ exposure was very similar in the presence and absence of R667 (Cmax = 50.8 vs 46.2 ng/mL; AUC0‐last = 215 vs 216 ng•h/mL; AUC0‐last ratio = 0.26 vs 0.26, respectively). R667 exposure was not affected by midazolam coadministration as compared with historical data. Based on the results of this study, no significant pharmacokinetic interaction should be anticipated between R667 and CYP3A4 substrates.

Effect of meal and antisecretory agents on the pharmacokinetics of danoprevir/ritonavir in healthy volunteers.

To evaluate the effect of a low‐ and high‐fat meal and co‐administration of ranitidine or omeprazole on the pharmacokinetics of ritonavir‐boosted danoprevir (DNVr).

Ritonavir-boosted danoprevir plus peginterferon alfa-2a and ribavirin in Asian chronic hepatitis C patients with or without cirrhosis.

Chronic hepatitis C is an important public health problem in Asia. We evaluated the safety, efficacy, and pharmacokinetics of fixed‐dose ritonavir‐boosted danoprevir plus peginterferon alfa‐2a/ribavirin in treatment‐naive Asian patients with chronic hepatitis C virus (HCV) genotype (G)1 infection.

Evaluation of the absolute bioavailability of pegylated interferon alfa-2a after subcutaneous administration to healthy male volunteers: an open-label, randomized, parallel-group study.

BACKGROUND Interferon (IFN)-based therapy is the recommended treatment for hepatitis C virus. Because pegylated IFN (PEG-IFN) alfa-2a is administered subcutaneously, it is of interest to determine the proportion of the dose that is absorbed from the subcutaneous (SC) tissue and ultimately reaches systemic circulation. OBJECTIVE The goal of this study was to characterize the absolute bioavailability of PEG-IFN alfa-2a (40 kDa) after SC dosing (180 μg) and to evaluate the pharmacokinetics of PEG-IFN alfa-2a after intravenous (IV) and SC administration. METHODS In this parallel-group study, 18 participants were given a single IV dose of PEG-IFN alfa-2a 90 μg and 18 participants received PEG-IFN alfa-2a 180 μg SC. Serum concentrations of PEG-IFN alfa-2a were measured predose and serially until 312 hours after the first dose. Pharmacokinetic parameters (CL/F, volume of distribution, C(max), and T(max)) were estimated using noncompartmental methods. Bioavailability was calculated by using the following formula: (AUC(SC)/AUC(IV)) · (dose(IV)/dose(SC)). RESULTS Eighteen healthy males received IV PEG-IFN alfa-2a, and an additional 18 healthy males received SC PEG-IFN alfa-2a. Subjects in each group had comparable mean weight, height, and body mass index. After IV administration of PEG-IFN alfa-2a (90 μg), there was a slow decline in serum concentration, the mean rate of systemic clearance was low at 126 mL/h, and the estimated mean volume of distribution at steady state was 9 L. After SC administration of PEG-IFN alfa-2a 180 μg, absorption was sustained, with mean T(max) occurring 102 hours after administration. The mean absolute bioavailability was 84%. A higher rate of influenza-like symptoms was observed after IV administration, along with decreased neutrophil counts, compared with subjects who underwent SC dosing. CONCLUSIONS Approximately 84% of a SC-administered dose of PEG-IFN alfa-2a reached the systemic circulation in these male healthy volunteers. The slow absorption, restricted distribution, and slow elimination of PEG-IFN alfa-2a resulted in sustained serum levels throughout the 7-day dosing interval.

Effect of Ritonavir‐Boosted Danoprevir, a Potent Hepatitis C Virus Protease Inhibitor, on the Pharmacokinetics of Methadone in Healthy Subjects Undergoing Methadone Maintenance Therapy

To investigate the steady‐state pharmacokinetics of methadone when coadministered with ritonavir‐boosted danoprevir (DNVr).

A grapefruit a day for patients infected with hepatitis C

prevent the overestimation of TE values due to necroinflammation. Indeed, it is well established that the degree of necroinflammation determined by histologic analysis and by analysis of biochemical activity are not necessarily correlated. We have some difficulties in understanding the contribution of TE in the clinical assessment of acute liver damage proposed by Panos et al., and especially its clinical usefulness, in terms of diagnosis and prognosis, in respect to the standard clinical assessment. In particular, two suggestions of these authors—namely, the use of TE for detecting the worsening of acute hepatitis and its possible evolution toward a fulminant form and for perceiving the presence of a “dual infection” hepatopathy—are at present merely hypothetical and need to be adequately substantiated. We agree that TE could be employed for monitoring disease recurrence in orthotopic liver transplantation patients. However, this methodology needs to be further evaluated in the clinical setting before being suggested as a reliable diagnostic tool. Indeed, results obtained in patients who have not undergone transplantation are not directly transferable to patients who have undergone transplantation, who show a different pattern of fibrotic evolution and a possible concomitant graft damage due to chronic rejection. Finally, we agree with Panos and colleagues that TE represents an exciting area of research and a potential source of innovation for the clinical practice of hepatology. Ideally, efforts should be directed at clarifying the presence and role of additional interfering or confounding factors. In this contention, the impact of cholestasis on liver stiffness (in part suggested by the data by Sagir et al.2) certainly deserves further investigation. Eventually, integration of TE with other noninvasive measures of disease progression will likely lead to a more comprehensive clinical assessment of patients with chronic liver disease. FRANCESCO VIZZUTTI, M.D., PH.D.1 UMBERTO ARENA, M.D.1 MASSIMO PINZANI, M.D., PH.D.1,2 ON BEHALF OF THE OTHER

Identification of new oral dosing regimens for the neuraminidase inhibitor oseltamivir in patients with moderate and severe renal impairment

Availability of lower‐dose oseltamivir capsules, an increased pharmacokinetic database, and a desire to align drug exposure across the spectrum of renal function prompted reassessment of oral dosing in patients with renal impairment. The data set comprised 128 subjects (71 with varying degrees of renal impairment) from 8 studies, which included single and multiple doses of 20–1000 mg. Pharmacokinetic profiles of oseltamivir phosphate (OP) and oseltamivir carboxylate (OC) were modeled simultaneously in NONMEM. Exposure metrics of OP and OC (AUC48 h, Cmax, Cmin) after administration of various dosing regimens were simulated for renal impairment subgroups and compared with exposures in patients with normal renal function receiving approved regimens. For influenza treatment, 30 mg once‐daily and twice‐daily regimens were selected for severe and moderate impairment, respectively. These regimens provided OC exposures similar or above those of the approved 75‐mg twice‐daily treatment regimen in subjects with normal renal function. For influenza prophylaxis, 30 mg once every other day and once‐daily regimens were selected for severe and moderate impairment, respectively. No dosing adjustments were required for mild impairment. This analysis supported revised labeling in the United States and Europe for oral oseltamivir dosing in patients with moderate and severe renal impairment.