Rolf van Heeswijk

Telaprevir for retreatment of HCV infection.

BACKGROUND Up to 60% of patients with hepatitis C virus (HCV) genotype 1 infection do not have a sustained virologic response to therapy with peginterferon alfa plus ribavirin. METHODS In this randomized, phase 3 trial, we evaluated the addition of telaprevir to peginterferon alfa-2a plus ribavirin in patients with HCV genotype 1 infection who had no response or a partial response to previous therapy or who had a relapse after an initial response. A total of 663 patients were assigned to one of three groups: the T12PR48 group, which received telaprevir for 12 weeks and peginterferon plus ribavirin for a total of 48 weeks; the lead-in T12PR48 group, which received 4 weeks of peginterferon plus ribavirin followed by 12 weeks of telaprevir and peginterferon plus ribavirin for a total of 48 weeks; and the control group (PR48), which received peginterferon plus ribavirin for 48 weeks. The primary end point was the rate of sustained virologic response, which was defined as undetectable HCV RNA 24 weeks after the last planned dose of a study drug. RESULTS Rates of sustained virologic response were significantly higher in the two telaprevir groups than in the control group among patients who had a previous relapse (83% in the T12PR48 group, 88% in the lead-in T12PR48 group, and 24% in the PR48 group), a partial response (59%, 54%, and 15%, respectively), and no response (29%, 33%, and 5%, respectively) (P<0.001 for all comparisons). Grade 3 adverse events (mainly anemia, neutropenia, and leukopenia) were more frequent in the telaprevir groups than in the control group (37% vs. 22%). CONCLUSIONS Telaprevir combined with peginterferon plus ribavirin significantly improved rates of sustained virologic response in patients with previously treated HCV infection, regardless of whether there was a lead-in phase. (Funded by Tibotec and Vertex Pharmaceuticals; REALIZE ClinicalTrials.gov number, NCT00703118.).

The Diarylquinoline TMC207 for Multidrug-Resistant Tuberculosis

BACKGROUND The diarylquinoline TMC207 offers a new mechanism of antituberculosis action by inhibiting mycobacterial ATP synthase. TMC207 potently inhibits drug-sensitive and drug-resistant Mycobacterium tuberculosis in vitro and shows bactericidal activity in patients who have drug-susceptible pulmonary tuberculosis. METHODS In the first stage of a two-stage, phase 2, randomized, controlled trial, we randomly assigned 47 patients who had newly diagnosed multidrug-resistant pulmonary tuberculosis to receive either TMC207 (400 mg daily for 2 weeks, followed by 200 mg three times a week for 6 weeks) (23 patients) or placebo (24 patients) in combination with a standard five-drug, second-line antituberculosis regimen. The primary efficacy end point was the conversion of sputum cultures, in liquid broth, from positive to negative. RESULTS The addition of TMC207 to standard therapy for multidrug-resistant tuberculosis reduced the time to conversion to a negative sputum culture, as compared with placebo (hazard ratio, 11.8; 95% confidence interval, 2.3 to 61.3; P=0.003 by Cox regression analysis) and increased the proportion of patients with conversion of sputum culture (48% vs. 9%). The mean log(10) count of colony-forming units in the sputum declined more rapidly in the TMC207 group than in the placebo group. No significant differences in average plasma TMC207 concentrations were noted between patients with and those without culture conversion. Most adverse events were mild to moderate, and only nausea occurred significantly more frequently among patients in the TMC207 group than among patients in the placebo group (26% vs. 4%, P=0.04). CONCLUSIONS The clinical activity of TMC207 validates ATP synthase as a viable target for the treatment of tuberculosis. (ClinicalTrials.gov number, NCT00449644.)

Effect of telaprevir on the pharmacokinetics of cyclosporine and tacrolimus

The hepatitis C virus protease inhibitor telaprevir is an inhibitor of the enzyme cytochrome P450 3A, responsible for the metabolism of both cyclosporine and tacrolimus. This Phase I, open‐label, nonrandomized, single‐sequence study assessed the effect of telaprevir coadministration on the pharmacokinetics of a single dose of either cyclosporine or tacrolimus in two separate panels of 10 healthy volunteers each. In Part A, cyclosporine was administered alone as a single 100‐mg oral dose, followed by a minimum 8‐day washout period, and subsequent coadministration of a single 10‐mg oral dose of cyclosporine with either a single dose of telaprevir (750 mg) or with steady‐state telaprevir (750 mg every 8 hours [q8h]). In Part B, tacrolimus was administered alone as a single 2‐mg oral dose, followed by a minimum 14‐day washout period, and subsequent coadministration of a single 0.5‐mg dose of tacrolimus with steady‐state telaprevir (750 mg q8h). Coadministration with steady‐state telaprevir increased cyclosporine dose‐normalized (DN) exposure (DN_AUC0‐∞) by approximately 4.6‐fold and increased tacrolimus DN_AUC0‐∞ by approximately 70‐fold. Coadministration with telaprevir increased the terminal elimination half‐life (t½) of cyclosporine from a mean (standard deviation [SD]) of 12 (1.67) hours to 42.1 (11.3) hours and t½ of tacrolimus from a mean (SD) of 40.7 (5.85) hours to 196 (159) hours. Conclusion: In this study, telaprevir increased the blood concentrations of both cyclosporine and tacrolimus significantly, which could lead to serious or life‐threatening adverse events. Telaprevir has not been studied in organ transplant patients; its use in these patients is not recommended because the required studies have not been completed to understand appropriate dose adjustments needed for safe coadministration of telaprevir with cyclosporine or tacrolimus, and regulatory approval has not been obtained. (HEPATOLOGY 2011;)

Multidrug-Resistant Tuberculosis and Culture Conversion with Bedaquiline

BACKGROUND Bedaquiline (Sirturo, TMC207), a diarylquinoline that inhibits mycobacterial ATP synthase, has been associated with accelerated sputum-culture conversion in patients with multidrug-resistant tuberculosis, when added to a preferred background regimen for 8 weeks. METHODS In this phase 2b trial, we randomly assigned 160 patients with newly diagnosed, smear-positive, multidrug-resistant tuberculosis to receive either 400 mg of bedaquiline once daily for 2 weeks, followed by 200 mg three times a week for 22 weeks, or placebo, both in combination with a preferred background regimen. The primary efficacy end point was the time to sputum-culture conversion in liquid broth. Patients were followed for 120 weeks from baseline. RESULTS Bedaquiline reduced the median time to culture conversion, as compared with placebo, from 125 days to 83 days (hazard ratio in the bedaquiline group, 2.44; 95% confidence interval, 1.57 to 3.80; P<0.001 by Cox regression analysis) and increased the rate of culture conversion at 24 weeks (79% vs. 58%, P=0.008) and at 120 weeks (62% vs. 44%, P=0.04). On the basis of World Health Organization outcome definitions for multidrug-resistant tuberculosis, cure rates at 120 weeks were 58% in the bedaquiline group and 32% in the placebo group (P=0.003). The overall incidence of adverse events was similar in the two groups. There were 10 deaths in the bedaquiline group and 2 in the placebo group, with no causal pattern evident. CONCLUSIONS The addition of bedaquiline to a preferred background regimen for 24 weeks resulted in faster culture conversion and significantly more culture conversions at 120 weeks, as compared with placebo. There were more deaths in the bedaquiline group than in the placebo group. (Funded by Janssen Pharmaceuticals; TMC207-C208 ClinicalTrials.gov number, NCT00449644.).

Telaprevir Alone or With Peginterferon and Ribavirin Reduces HCV RNA in Patients With Chronic Genotype 2 but Not Genotype 3 Infections

BACKGROUND & AIMS We evaluated antiviral activity of 2 weeks therapy with telaprevir alone, peginterferon alfa-2a and ribavirin (PR), or all 3 drugs (TPR) in treatment-naïve patients with chronic hepatitis C virus (HCV) genotype 2 or 3 infections. METHODS We performed a randomized, multicenter, partially blinded study of patients (23 with HCV genotype 2, 26 with genotype 3) who received telaprevir (750 mg every 8 h), placebo plus PR (peginterferon, 180 μg, once weekly and ribavirin, 400 mg, twice daily), or TPR for 15 days, followed by PR for 22 or 24 weeks. Plasma levels of HCV RNA were quantified. RESULTS Levels of HCV RNA decreased in all patients with HCV genotype 2, including those who received telaprevir monotherapy. The decrease was more rapid among patients who received telaprevir. By day 15, 0% (telaprevir), 40% (TPR), and 22% (PR) of patients with HCV genotype 2 had undetectable levels of HCV RNA; rates of sustained virologic response were 56%, 100%, and 89%, respectively. Overall, 6 of 9 HCV genotype 2 patients that received only telaprevir had viral breakthrough within 15 days after an initial response. HCV RNA levels decreased slightly among patients with HCV genotype 3 who received telaprevir and decreased rapidly among patients given PR or TPR (telaprevir had no synergistic effects with PR). Sustained virologic response rates were 50%, 67%, and 44% among patients given telaprevir, TPR, or PR respectively; 7 patients with HCV genotype 3 relapsed after therapy (2 given telaprevir, 3 given TPR, and 2 given PR) and 3 patients with HCV genotype 3 had viral breakthrough during telaprevir monotherapy. The incidence of adverse events was similar among groups. CONCLUSIONS Telaprevir monotherapy for 2 weeks reduces levels of HCV RNA in patients with chronic HCV genotype 2 infections, but has limited activity in patients with HCV genotype 3.

Telaprevir Is Effective Given Every 8 or 12 Hours With Ribavirin and Peginterferon Alfa-2a or -2b to Patients With Chronic Hepatitis C

BACKGROUND & AIMS Recent studies have shown that 12 weeks of treatment with telaprevir, administered every 8 hours (q8h), combined with pegylated interferon (peginterferon) alfa-2a plus ribavirin significantly increased the rate of hepatitis C virus (HCV) eradication (sustained virologic response [SVR]) in patients infected with HCV genotype 1 compared with approved therapy. We investigated the efficacy, safety, tolerability, and pharmacokinetics of telaprevir given q8h or every 12 hours (q12 h) in combination with peginterferon alfa-2a or alfa-2b. METHODS Treatment-naive patients (n = 161) infected with HCV genotype 1 were randomly assigned to groups that were given open-label telaprevir (750 mg q8 h or 1125 mg q12 h) in combination with standard doses of peginterferon alfa-2a (180 μg/wk) and ribavirin (1000-1200 mg/day) or peginterferon alfa-2b (1.5 μg·kg(-1)·wk(-1)) and ribavirin (800-1200 mg/day). Patients received triple therapy for 12 weeks, followed by 12 or 36 additional weeks of treatment with peginterferon alfa and ribavirin, based on virologic response. RESULTS Baseline characteristics were similar for all groups. SVR rates were 81.0% to 85.0% among groups; most patients received 24 weeks of therapy (68.0%). There were no significant differences in SVR rates (intent-to-treat analysis) among groups (P ≥ .787), between the pooled q8 h and q12 h groups (P = .997), or between the pooled peginterferon alfa-2a/ribavirin and peginterferon alfa-2b/ribavirin groups (P = .906). The safety profile was similar among all groups. CONCLUSIONS A high proportion (>80%) of patients achieved an SVR regardless of the telaprevir dosing frequency (q8 h or q12 h) or type of peginterferon alfa used (alfa-2a or alfa-2b).

Effect of the Hepatitis C Virus Protease Inhibitor Telaprevir on the Pharmacokinetics of Amlodipine and Atorvastatin

ABSTRACT Telaprevir is a hepatitis C virus protease inhibitor that is both a substrate and an inhibitor of CYP3A. Amlodipine and atorvastatin are both substrates of CYP3A and are among the drugs most frequently used by patients with hepatitis C. This study was conducted to examine the effect of telaprevir on atorvastatin and amlodipine pharmacokinetics (PK). This was an open-label, single sequence, nonrandomized study involving 21 healthy male and female volunteers. A coformulation of 5 mg amlodipine and 20 mg atorvastatin was administered on day 1. Telaprevir was taken with food as a 750-mg dose every 8 h from day 11 until day 26, and a single dose of the amlodipine-atorvastatin combination was readministered on day 17. Plasma samples were collected for determination of the PK of telaprevir, amlodipine, atorvastatin, ortho-hydroxy atorvastatin, and para-hydroxy atorvastatin. When administration with telaprevir was compared with administration without telaprevir, the least-square mean ratios (90% confidence limits) for amlodipine were 1.27 (1.21, 1.33) for the maximum drug concentration in serum (Cmax) and 2.79 (2.58, 3.01) for the area under the concentration-time curve from 0 h to infinity (AUC0-∞); for atorvastatin, they were 10.6 (8.74, 12.9) for the Cmax and 7.88 (6.84, 9.07) for the AUC0-∞. Telaprevir significantly increased exposure to amlodipine and atorvastatin, consistent with the inhibitory effect of telaprevir on the CYP3A-mediated metabolism of these agents.

Limited impact of IL28B genotype on response rates in telaprevir-treated patients with prior treatment failure

BACKGROUND & AIMS Nucleotide polymorphisms upstream of the interleukin 28B (IL28B) gene are strongly associated with hepatitis C virus (HCV) clearance in treatment-naïve patients treated with peginterferon/ribavirin (PegIFN/RBV). This subanalysis of the REALIZE study evaluated the impact of IL28B polymorphisms on sustained virologic response (SVR) in telaprevir-treated, HCV genotype 1-infected patients with prior PegIFN/RBV treatment failure. METHODS Treatment-experienced patients were randomized to 12 weeks of telaprevir (750 mg every 8h) with/without a 4-week PegIFN/RBV lead-in, or placebo, each with PegIFN-α-2a (180 μg/week) and ribavirin (1000-1200 mg/day) for 48 weeks overall. Data from telaprevir arms were pooled. RESULTS Eighty percent (527/662) of patients consented to genetic testing and were included. Similar proportions of patients had IL28B CC, CT and TT genotypes across treatment arms; baseline characteristics were generally well balanced. SVR rates were higher in the pooled telaprevir versus placebo group for all IL28B genotypes; CC: 79% versus 29%, respectively; CT: 60% versus 16%, respectively; TT: 61% versus 13%, respectively. Within each prior response category (relapse, partial or null response), SVR and viral breakthrough rates with telaprevir-based treatment were comparable across IL28B genotypes. IL28B genotype did not significantly affect SVR (2-step multivariate analyses; p >0.16 in pairwise comparison among CC, TT, and CT). Variations in rapid virologic response and relapse rates were noted in certain patient subgroups. CONCLUSIONS Our findings suggest that IL28B genotype has a limited impact on SVR rates with telaprevir-based therapy in treatment-experienced patients. IL28B genotyping may have limited utility in the baseline evaluation of similar patients considered for telaprevir-based therapy.

Effect of Telaprevir on the Pharmacokinetics of Midazolam and Digoxin

In this open‐label study, 24 healthy volunteers received a single intravenous (IV) dose of 0.5 mg of midazolam on day 1 and a single oral dose each of 2 mg of midazolam and 0.5 mg of digoxin on day 3. Telaprevir 750 mg every 8 hours was administered from day 8 through day 23, along with a single IV dose of 0.5 mg of midazolam on day 17 and single oral doses of 2 mg of midazolam and 0.5 mg of digoxin on day 19. Midazolam, 1′‐hydroxymidazolam, digoxin, and telaprevir concentrations in plasma and digoxin concentrations in urine were measured and pharmacokinetic parameters calculated. On comparing administration with versus without telaprevir, the geometric least squares mean ratios (with 90% confidence limits) for IV midazolam were 1.02 (0.80, 1.31) for maximum observed concentrations (Cmax) and 3.40 (3.04, 3.79) for area under the curve from 0 to 24 hours (AUC0–24h); for oral midazolam 2.86 (2.52, 3.25) for Cmax and 8.96 (7.75, 10.35) for AUC0–24h; and for oral digoxin 1.50 (1.36, 1.65) for Cmax and 1.85 (1.70, 2.00) for area under the curve from 0 to infinity (AUC0‐∞). Coadministration of telaprevir with oral midazolam resulted in approximately 3‐fold decrease in the mean AUC0‐∞ of 1′‐hydroxymidazolam. The renal clearance of digoxin was similar with or without telaprevir. Results show that telaprevir is an inhibitor of CYP3A and P‐glycoprotein.

The effect of CYP3A inhibitors and inducers on the pharmacokinetics of telaprevir in healthy volunteers.

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