Mark Laughlin

Pharmacokinetics, safety, and tolerability of oral posaconazole administered in single and multiple doses in healthy adults.

ABSTRACT The pharmacokinetics, safety, and tolerability of posaconazole, an investigational triazole antifungal, were evaluated following the administration of rising single and multiple oral doses. A total of 103 healthy adults were enrolled in two phase I trials. Each study had a double-blind, placebo-controlled, parallel-group design with a rising single-dose (RSD) or rising multiple-dose (RMD) scheme. In the RSD study, subjects received single doses of posaconazole oral tablets (50 to 1,200 mg) or placebo. In the RMD study, subjects received posaconazole oral tablets (50 to 400 mg) or placebo twice daily for 14 days. By using model-independent methods, the area under the plasma concentration-time curve and the maximum concentration in plasma were determined and used to assess dose proportionality. In the RSD study, the levels of posaconazole in plasma increased proportionally between the 50- and 800-mg dose range, with saturation of absorption occurring above 800 mg. Dose proportionality was also observed in the RMD study. In both studies, the apparent volume of distribution was large (range, 343 to 1,341 liters) and the terminal-phase half-life was long (range, 25 to 31 h). Posaconazole was well tolerated at all dose levels, and the adverse events were not dose dependent. No clinically significant changes in clinical laboratory test values or electrocardiograms were observed. Following the administration of single and twice-daily rising doses, the level of posaconazole exposure increased in a dose-proportional manner. The long elimination-phase half-life of posaconazole supports once- or twice-daily dosing in clinical trials; however, additional studies are required to determine if further division of the dose will enhance exposure.

Oral bioavailability of posaconazole in fasted healthy subjects: comparison between three regimens and basis for clinical dosage recommendations.

Background and objectivePosaconazole is a potent, extended-spectrum triazole antifungal agent currently in clinical development for the treatment of invasive fungal infections. This study was conducted to compare the bioavailability and resulting serum concentrations of posaconazole 800mg following administration of three different dose regimens to fasting adults.Study designThis was a randomised, open-label, three-way crossover study.MethodsSubjects fasted 12 hours before and 48 hours after the administration of posaconazole oral suspension (800mg) given as a single dose (regimen A), 400mg every 12 hours (regimen B) or 200mg every 6 hours (regimen C). Plasma posaconazole concentrations were determined for 48 hours after the initial dose and subjects completed a 1-week washout period between treatment regimens. A one-compartment oral model with first-order rate of absorption and first-order rate of elimination was fitted to the plasma concentration-time data. Differences in exposure were investigated by allowing the bioavailability fraction to vary among regimens.Study participantsA total of 18 healthy men were enrolled in and completed the study.Main outcome measures and resultsPosaconazole relative bioavailability was estimated to be significantly different among regimens (p < 0.0001) and increased with the number of doses, such that regimen B/regimen A = 1.98 ± 0.35, representing a 98% increase, and regimen C/regimen A = 3.20 ± 0.69, or a 220% increase. With use of the one-compartment model, the population steady-state values for area under the concentration-time curve over 24 hours were predicted to be 3900, 7700 and 12 400 μg · h/L, with average plasma concentrations of 162, 320 and 517 μg/L for regimens and C, respectively.ConclusionThese data suggest that divided daily dose administration (every 12 or 6 hours) significantly increases posaconazole exposure under fasted conditions.

Pharmacokinetics of Posaconazole Coadministered with Antacid in Fasting or Nonfasting Healthy Men

ABSTRACT Posaconazole is a potent broad-spectrum azole antifungal agent in clinical development for the treatment of invasive fungal infections. This study evaluated the potential for a pH-dependent pharmacokinetic interaction between posaconazole and an antacid (Mylanta), under fasting and nonfasting conditions. Twelve men completed this randomized, four-period crossover, single-dose study. Subjects received 200 mg of posaconazole following a 10-h fast, with 20 ml of Mylanta and a 10-h fast, with 20 ml of Mylanta and a high-fat breakfast, and with a high-fat breakfast alone. Antacid coadministration had no statistically significant effects on posaconazole bioavailability under fasting or nonfasting conditions. In the fasting state, antacid slightly increased the relative oral bioavailability of posaconazole by 15% (P = 0.296); in the nonfasting state, antacid decreased the relative bioavailability of posaconazole by 12% (P = 0.352). Food increased the relative oral bioavailability of posaconazole by 400% (P = 0.001). In conclusion, the effect of antacid on posaconazole exposure in the fasting or nonfasting state was small and is not considered clinically significant.

Interferon alfa‐2b in combination with ribavirin for the treatment of chronic hepatitis C in children: Efficacy, safety, and pharmacokinetics

Chronic hepatitis C virus (HCV) infection is usually asymptomatic in children, but significant liver disease may occur. We evaluated the efficacy, safety, and pharmacokinetics of interferon alfa‐2b and ribavirin in children with chronic HCV. We determined the optimal ribavirin dose in an initial cohort of a phase 1 study and then subsequently used it, in combination with interferon alfa‐2b, in a second cohort of this study and a phase 3 trial. The primary efficacy endpoint in all studies was sustained virological response, defined by undetectable serum HCV RNA 24 weeks after completion of therapy. All efficacy and safety analyses were performed on the intent‐to‐treat population. Children receiving interferon alfa‐2b plus ribavirin 15 mg/kg/d in the phase 1 study had the maximum reduction in serum HCV RNA at treatment weeks 4 and 12 with an acceptable safety profile. This ribavirin dose was selected as optimal and used in all subsequent studies. In all, 46% (54/118) of optimally treated children achieved sustained virological response. Sustained virological response was significantly higher in children with HCV genotype 2/3 (84%) than in those with HCV genotype 1 (36%). Adverse events led to dose modification in 37 (31%) and discontinuation in 8 (7%). Multiple‐dose interferon alfa‐2b and ribavirin peak and trough concentrations and area‐under‐the‐curve were similar between children and adults. In conclusion, interferon alfa‐2b in combination with ribavirin is effective and safe in children with chronic hepatitis C virus. (HEPATOLOGY 2005;42:1010–1018.)

Posaconazole pharmacokinetics, safety, and tolerability in subjects with varying degrees of chronic renal disease.

Posaconazole is a triazole antifungal in development for the treatment of invasive fungal infections. The authors evaluated the pharmacokinetics and safety of posaconazole in healthy subjects and in those with mild (CLCR = 50–80 mL/min), moderate (CLCR = 20–49 mL/min), and severe chronic renal disease (CLCR <20 mL/min; receiving outpatient hemodialysis) (n = 6/group). Subjects received one 400‐mg dose of posaconazole oral suspension with a standardized high‐fat breakfast. For hemodialysis‐dependent subjects, this dose was given on a nonhemodialysis day, and a second 400‐mg dose was given 6 hours before hemodialysis. Blood samples were collected before dose and up to 120 hours postdose. For hemodialysis‐dependent subjects following the second dose, additional samples (predialyzed and postdialyzed) were collected before, during, and after dialysis. There was no correlation between posaconazole pharmacokinetics and mild to moderate renal disease; the slopes of the linear regressions for creatinine clearance versus posaconazole AUC, Cmax, CL/F, and t1/2 values were not significantly different from zero (P > .130). Mean CL/F values before and during hemodialysis were comparable. Furthermore, the difference in the predialyzed and postdialyzed posaconazole concentrations was only ∼3%, supporting that posaconazole was not removed by hemodialysis. Protein binding was similar in all groups (∼98%) and was unaffected by hemodialysis. Posaconazole was generally well tolerated. One patient had elevated liver function test results that were not present at baseline and were thought to be possibly related to posaconazole. Results of this single‐dose study indicate that dosage adjustments for patients with varying degrees of renal disease are not required.

Ribavirin dosing in chronic hepatitis C: Application of population pharmacokinetic-pharmacodynamic models

Combination therapy of ribavirin with interferon alfa‐2b and pegylated interferon alfa‐2b is currently approved for the treatment of chronic hepatitis C. Approved ribavirin dosages vary from a fixed dosage of 800 mg/d to as much as 1200 mg/d on the basis of body weight.

Use of high-performance liquid chromatographic and microbiological analyses for evaluating the presence or absence of active metabolites of the antifungal posaconazole in human plasma.

Posaconazole (SCH 56592) is a novel broad spectrum triazole antifungal agent that is currently in phase III clinical trials for the treatment of systemic fungal infections. This study was initiated to determine if orally administered posaconazole to humans would result in the formation of active metabolite(s). Plasma samples from a multiple-rising dose study in healthy volunteers were analyzed by validated HPLC and microbiological methods. The HPLC analysis involved extraction with a mixture of organic solvent (methylene chloride-hexane) followed by separation on a C18 column and quantification by UV absorbance at 262 nm. The microbiological assay was performed utilizing an agar diffusion method using Candida pseudorropicalis ATCC 46764 as the test organism. Potency was determined by comparing the growth inhibition zones produced by the test sample to those produced by standard concentrations prepared in plasma. Individual and mean plasma concentration-time profiles were similar for both HPLC and microbiological assays. The area under the plasma concentration-time curves of the microbiological and HPLC results were similar with a mean (RSD) ratio of 105.5% 15.3%), indicating that there was no relevant biologically active metabolite of posaconazole in human plasma.

Treating fungal infections.

SIR,-We have read with interest the article by Professor A E H Emery and Mr D Burt (9 February, p 355) on the occurrence of eosinophilic muscle fibres and increased intracellular calcium in Duchenne muscular dystrophy and in fetuses at risk for the disease and would like to comment on some of their observations and interpretations. The authors state that these features are useful for identifying dystrophic fetuses and imply that increased calcium may relate to the primary defect, but we feel that caution is needed before these conclusions can be reached.

Chiral high‐performance liquid chromatographic analysis of antifungal SCH 56592 and evaluation of its chiral inversion in animals and humans

SCH 56592 is a novel triazole antifungal agent that is active both orally and intravenously in animal models of infection. This compound is in Phase II-III clinical trials for the treatment of systemic fungal infections. SCH 56592 is a single enantiomer with four stereogenic centers; therefore, it was necessary to evaluate the possible chiral inversion of this drug candidate in animals and humans. Thus, chiral high-performance liquid chromatographic (HPLC) methods have been developed to separate SCH 56592 from its diastereomers and to evaluate its chiral inversion in rats, dogs, cynomolgus monkeys, and humans. Chiral HPLC analysis involved the use of a Chiralcel OD column set at 39 degrees C with a mobile phase of hexane-ethanol-diethylamine and a fluorescence detector set at an excitation wavelength of 270 nm and an emission wavelength of 390 nm. Plasma or serum samples were subjected to solid phase extraction on a C(2) cartridge followed by HPLC analysis. The method was sensitive with a limit of quantitation of 0.1 microg/ml in dog serum. The linearity was satisfactory, as shown by correlations of >0.997 and by visual examination of the calibration curves. The precision and accuracy were satisfactory, as indicated by coefficients of variation (CV) ranging from 1.1 to 12.1% and bias values ranging from -11.0 to 9.0%. Chiral HPLC analysis indicated that SCH 56592 was not subjected to chiral inversion in rats, dogs, cynomolgus monkeys, and humans.

Optimal Dosing Frequency of Pegylated Interferon Alfa-2b Monotherapy for Chronic Hepatitis C Virus Infection

BACKGROUND & AIMS Pegylated interferon alfa-2b (PEG-IFN-alfa 2b ) has been shown to provide superior efficacy to IFN-alfa 2b in patients with chronic hepatitis C (predominantly genotype 1) infection as measured by viral clearance. This study was conducted to determine the optimal dosing regimen of PEG-IFN-alfa 2b required to obtain a maximum decrease of hepatitis C viral RNA. METHODS This was a 24-week, open-label, multicenter, parallel-group, randomized, active-controlled trial in the United Kingdom, France, and Israel. Individuals (n = 61) with chronic hepatitis C infection, genotype 1, received IFN-alfa 2b 3 mIU 3 times weekly for 24 weeks, or PEG-IFN-alfa 2b 1.5 or 3.0 microg/kg/wk, as total weekly full or split doses, for 12 weeks. At week 12, serum RNA titer was measured, and all PEG-IFN-alfa 2b patients continued with 1.5 microg/kg/wk for a further 12 weeks. RESULTS Mean serum hepatitis C RNA levels decreased in all groups at weeks 12 and 24. PEG-IFN-alfa 2b 1.5 microg/kg/wk was superior to IFN-alfa 2b in decreasing mean serum hepatitis C RNA ( P < .05 at week 12). The efficacy of split-dose PEG-IFN-alfa 2b 1.5 or 3.0 microg/kg/wk regimens was not significantly different from full-dose PEG-IFN-alfa 2b 1.5 microg/kg/wk. However, there was a significant decrease in neutrophil count in groups receiving PEG-IFN-alfa 2b 3.0 microg/kg/wk or lower, multiple-dose per week regimens. CONCLUSIONS PEG-IFN-alfa 2b 1.5 microg/kg once weekly is the optimal dosing frequency for patients with chronic hepatitis C with predominantly genotype 1 infection. More frequent dosing or increasing the dose to 3.0 microg/kg/wk did not result in improved antiviral effects, but did decrease neutrophil counts.