Enzyme induction observed in healthy volunteers after repeated administration of rifapentine and its lack of effect on steady-state rifapentine pharmacokinetics: part I.

OBJECTIVE: To determine the effects of rifapentine on hepatic mixed function oxidase activity and to assess the effect of enzyme induction on the steady-state pharmacokinetics of rifapentine. STUDY DESIGN: Twenty-three healthy males were randomized to receive two of the following treatments in a two-period, four-treatment, incomplete block, crossover design: single daily oral rifapentine doses of 150 mg (group A), 300 mg (group B), or 600 mg (group C) on study days 1 and 4-10, or single oral rifapentine 600 mg doses given every 3 days for a total of four doses (group D). Serial blood samples were collected after the first and last rifapentine dose and assayed for rifapentine and its active metabolite, 25-desacetyl-rifapentine. Urine was collected for determination of cortisol and 6-hydroxycortisol concentrations. RESULTS: The ratio of 6beta-hydroxycortisol:cortisol increased during rifapentine administration (+229%, +317%, and +357% on day 10 for groups A, B, and C, respectively). Ratios returned to baseline 2 weeks after the last dose. The per cent increase in the ratio of 6beta-hydroxycortisol:cortisol following daily doses (+357%) was much higher compared with every 72-hour dosing (+236%). Single-dose and steady-state comparisons of AUCss(0-24) and AUC(0-->infinity) for both rifapentine and 25-desacetyl-rifapentine were similar (P = NS) at corresponding doses of rifapentine. Mean t(1/2) at steady-state was 84-98% of corresponding single-dose values. CONCLUSION: Rifapentine is a potent inducer of CYP3A activity. However, single-dose pharmacokinetics of rifapentine predict steady-state exposure, indicating no autoinduction of rifapentine metabolism with repeated administration. Enzyme activity returns to predose levels within 2 weeks of the last daily dose of rifapentine.

Single and multiple dose pharmacokinetics of rifapentine in man: part II.

OBJECTIVE: To characterize the pharmacokinetics of rifapentine following single, multiple, and intermittent doses. DESIGN: Twenty-three healthy male volunteers were randomized in a two-period, incomplete block, crossover design to receive two of four possible treatments: single daily oral rifapentine doses of 150, 300, or 600 mg given on day 1 and again on days 4-10, or a single oral 600 mg dose given on days 1, 4, 7, and 10. RESULTS: Maximum rifapentine plasma concentrations were observed in 4-5 hours. Mean rifapentine t(1/2) ranged from 13.2-14.1 hours and was similar across the 150-600 mg dose range. The changes in rifapentine Cmax (R = 0.86) and AUC(0-->infinity) (R + 0.90) were dose linear. The active 25-desacetyl metabolite appeared slowly in plasma, with mean Tmax of 14.4-17.8 hours. Mean t(1/2) for 25-desacetyl-rifapentine ranged from 13.3-24.3 hours. Disproportionate, dose-dependent increases in rifapentine and 25-desacetyl-rifapentine AUC were observed as single doses of rifapentine increased from 150 to 600 mg. At steady state, however, the magnitude of dose dependency was much less. CONCLUSION: Maximum plasma rifapentine concentrations were well above minimum inhibitory concentrations for Mycobacterium tuberculosis and M. avium following single 600 mg doses. In addition, the extended t(1/2) of rifapentine and its active metabolite support clinical investigation of once or twice-weekly rifapentine dosage regimens of rifapentine for the management of tuberculosis.

Fragmentation of scheduled visits and missed doses among infants receiving multiple injected vaccines.

A retrospective cohort study was used to determine the extent to which immunisation visits due in the first year of life are split into separate visits. A one-month birth cohort of infants registered in early childhood health centres in the former Eastern Sydney Health Area was followed up when the infants were 8 to 11 months of age. A telephone questionnaire sought documented dates of each dose in the primary series of diphtheria-tetanus-pertussis (DTP), Haemophilus influenzae type b (Hib) and hepatitis B (HBV) vaccination. Of the 141 subjects, 130 had received all due doses of DTP and Hib vaccines and 63 (45 per cent) had been enrolled in the neonatal hepatitis B program. Infants in the latter group received the first DTP-Hib dose on average one week later than did those not in the hepatitis B program (DTP, P = 0.016; Hib, P = 0.047). The greatest percentage of missed DTP or Hib doses occurred in infants not receiving HBV vaccination (7.1 per cent of doses) or those high-risk infants enrolled in the neonatal hepatitis B program (2.9 per cent). Overall, 12 infants had 28 (6.9 per cent) of the 404 possible scheduled visits fragmented into two separate visits. In all cases, parents reported that this was at the suggestion of the general practitioner. We found no greater likelihood of fragmentation for infants who had also received hepatitis B vaccine. Only 17 infants (29 per cent) had received the third hepatitis B vaccine and DTP doses at the same visit, as recommended. These findings confirm anecdotal reports of fragmentation of scheduled visits and missed doses for infants due to receive multiple injections, and some delay in uptake among those receiving hepatitis B vaccine. Universal infant hepatitis B immunisation should not be considered until combination vaccines (which should also include a Hib component) become available in Australia.