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.

Pharmacokinetics of rifapentine in subjects seropositive for the human immunodeficiency virus: a phase I study.

Rifapentine is undergoing development for the treatment of pulmonary tuberculosis. This study was conducted to characterize the single-dose pharmacokinetics of rifapentine and its 25-desacetyl metabolite and to assess the effect of food on the rate and extent of absorption in participants infected with human immunodeficiency virus (HIV). Twelve men and four women, mean age, 38.6 +/- 6.9 years, received a single 600-mg oral dose of rifapentine in an open-label, randomized two-way, complete crossover study. Each volunteer received rifapentine following a high-fat breakfast or during a fasting period. Serial blood samples were collected for 72 h and both rifapentine and its metabolite were assayed by a validated high-performance liquid chromatography method. Pharmacokinetics of rifapentine and 25-desacetylrifapentine were determined by noncompartmental methods. Mean (+/- the standard deviation) maximum concentrations of rifapentine in serum and areas under the curve from time zero to infinity following a high-fat breakfast were 14.09 +/- 2.81 and 373.63 +/- 78.19 micrograms/ml, respectively, and following a fasting period they were 9.42 +/- 2.67 and 256.10 +/- 86.39 micrograms. h/ml, respectively. Pharmacokinetic data from a previously published healthy volunteer study were used for comparison. Administration of rifapentine with a high-fat breakfast resulted in a 51% increase in rifapentine bioavailability, an effect also observed in healthy volunteers. Although food increased the exposure of these patients to rifapentine, the infrequent dosing schedule for the treatment of tuberculosis (e.g., once- or twice-weekly dosing) would be unlikely to lead to accumulation. Additionally, autoinduction has been previously studied and has not been demonstrated with this compound, unlike with rifabutin and rifampin. Rifapentine was well tolerated by HIV-infected study participants. The results of our study suggest that no dosage adjustments may be required for rifapentine in HIV-infected patients (Centers for Disease Control and Prevention classification A1, A2, B1, or B2) undergoing treatment for tuberculosis.

Pharmacokinetics of dolasetron with coadministration of cimetidine or rifampin in healthy subjects.

PURPOSE: Dolasetron is a selective 5-HT3 receptor antagonist. The purpose of this study was to determine the effect of cimetidine and rifampin on the steady-state pharmacokinetics of orally administered dolasetron and its active reduced metabolite, hydrodolasetron. METHODS: A group of 18 healthy men (22 to 44 years old) were randomized to receive each of the following three treatments in a three-period cross-over design: 200 mg dolasetron daily (treatment A); 200 mg dolasetron daily plus 300 mg cimetidine four times daily (treatment B); or 200 mg dolasetron daily plus 600 mg rifampin daily (treatment C). Each study period was separated by a 14-day washout period. Serial blood samples were collected before the first dose (baseline) on day 1 and at frequent intervals up to 48 h after the morning dose on day 7 for quantification of dolasetron and its metabolites, hydrodolasetron (both isomers), 5'OH hydrodolasetron, and 6'OH hydrodolasetron. Serial urine samples were also collected at baseline and during the periods 0-24 and 24-48 h following the morning dose on day 7, and analyzed for dolasetron and its metabolites. RESULTS: Plasma and urine dolasetron concentrations were below quantifiable concentrations for all three treatments. Mean steady-state area under the plasma concentration-time curve (AUCss(0-24)) of hydrodolasetron increased by 24%, mean apparent clearance (CLapp.po) decreased by 19%, and maximum plasma hydrodolasetron concentration (Cmax,ss) increased by 15% when dolasetron was coadministered with cimetidine. When dolasetron was given with rifampin, mean hydrodolasetron AUCss(0-24) decreased by 28%, CLapp.po, increased by 39%, and hydrodolasetron Cmax,ss decreased by 17%. Small differences were found in mean tmax (0.7 to 0.8 h), CLr (2.0 to 2.6 ml/min per kg), and t1/2 (7.4 to 8.8 h) for hydrodolasetron between treatment periods. Approximately 20% and 2% of the dolasetron dose were excreted in urine as the R(+) isomer and S(-) isomer of hydrodolasetron, respectively, across all three treatments. Dolasetron mesylate was well tolerated in this study during all three treatment periods, with the highest incidence of adverse events reported during the control period when dolasetron mesylate was given alone. CONCLUSION: Based on the small changes in the pharmacokinetic parameters of dolasetron and its active metabolites, as well as the favorable safety results, no dosage adjustments for dolasetron mesylate are recommended with concomitant administration of cimetidine or rifampin.

Single-dose pharmacokinetics of rifapentine in women.

Gender can be an important variable in the absorption and disposition of some drugs. In this open-label study, 15 healthy, nonsmoking women received a single 600-mg oral dose of rifapentine. Plasma samples were obtained at frequent intervals for up to 72 hr after the dose to determine the pharmacokinetic (PK) parameters of rifapentine and its active metabolite, 25-desacetyl-rifapentine. Peak plasma rifapentine concentrations (Cmax) were observed 5.9 hr after ingestion of the single dose. The mean area under the rifapentine plasma concentration-time curve [AUC(0-->infinity)] was 325 micrograms.hr ml and the mean elimination half-life (t1/2) was 16.3 hr. Plasma concentrations for the 25-desacetyl metabolite peaked at 15.4 hr after the rifapentine dose and declined with a terminal half-life of 17.3 hr. These rifapentine and 25-desacetyl-rifapentine PK data in women were compared to data generated previously in healthy men. Striking similarities in the PK profiles of parent drug and metabolite were found in the two populations. Mean differences in rifapentine CL/F (12%) and t1/2 (2%) were small. The only adverse event reported in the female subjects was discoloration of the urine. Based on these PK and safety data, no dosage adjustments for rifapentine based on gender are recommended.

Disposition and metabolism of 14C-rifapentine in healthy volunteers.

Rifapentine is a long-acting cyclopentyl-derivative of rifampin. This study was designed to investigate the mass balance and biotransformation of 14C-rifapentine in humans. Four healthy male volunteers received a single 600-mg oral dose of 14C-rifapentine in a hydroalcoholic solution. Whole blood, urine, and fecal samples were collected before and at frequent intervals after drug administration. Amount of radioactivity recovered in urine and feces was assessed for up to 18 days postdose. Metabolite characterization in urine and feces was conducted using high-performance liquid chromatography with radiometric detection and liquid chromatography/mass spectroscopy. The total recovery of radioactive dose was 86.8%, with the majority of the radioactive dose recovered in feces (70.2%). Urine was a minor pathway for excretion (16.6% of the dose recovered). More than 90% of the excreted radioactivity was profiled as 14C chromatographic peaks and 50% was structurally characterized. These characterized compounds found in feces and urine were rifapentine, 25-desacetyl-rifapentine, 3-formyl-rifapentine, and 3-formyl-25-desacetyl-rifapentine. The 25-desacetyl metabolite, formed by esterase enzymes found in blood, liver, and other tissues, was the most abundant compound in feces and urine, contributing 22% to the profiled radioactivity in feces and 54% in urine. The 3-formyl derivatives of rifapentine and 25-desacetyl-rifapentine, formed by nonenzymatic hydrolysis, were also prominent in feces and, to a lesser extent, in urine. In contrast to the feces and urine, rifapentine and 25-desacetyl-rifapentine accounted for essentially all of the plasma radioactivity (99% of the 14C area under the concentration-time curve), indicating that 25-desacetyl-rifapentine is the primary metabolite in plasma. It appears, therefore, that the nonenzymatic hydrolysis of rifapentine to 3-formyl byproducts occurs primarily in the gut and the acidic environment of the urine.

Single-dose pharmacokinetics of rifapentine in elderly men.

PURPOSE: This study was undertaken to characterize the pharmacokinetic profiles of rifapentine and its active metabolite, 25-desacetlyl rifapentine, in elderly men. METHODS: Fourteen healthy, nonsmoking male volunteers between the ages of 65 and 82 years received a single oral 600 mg dose of rifapentine. Plasma samples were collected at frequent intervals for up to 72 hours postdose. The control group consisted of 20 healthy, young (18-45 years) males volunteers from a previous, single-dose (600 mg) rifapentine pharmacokinetic study. RESULTS: Plasma rifapentine concentrations above the minimum inhibitory concentration for M. tuberculosis were observed at 2 hours after dosing. Disposition of rifapentine was monophasic with a mean terminal half-life of 19.6 hours. The peak plasma concentration of 25 desacetyl-rifapentine was found 21.7 hours, on average, after the rifapentine dose; the mean 25-desacetyl-rifapentine t1/2 was 22.9 hours. Compared to the younger subjects, apparent oral clearance of rifapentine (24%) was lower in the elderly male (p < 0.05), and Cmax (28%) was higher. The only adverse event reported in both the older and younger subjects in these single-dose studies was discoloration of the urine. CONCLUSIONS: Because the aged-related changes in the pharmacokinetic profile of rifapentine observed in this study were modest and unlikely to be associated with toxicity, no dosage adjustments for this antibiotic are recommended in elderly patients.

Pharmacokinetics of rifapentine in patients with varying degrees of hepatic dysfunction.

In this open-label investigation, the pharmacokinetics of rifapentine and its active metabolite, 25-desacetyl-rifapentine, were characterized in patients with varying degrees of hepatic dysfunction. Eight patients with mild-to-moderate chronic, stable hepatic dysfunction and seven patients with moderate-to-severe hepatic dysfunction received single oral 600-mg doses of rifapentine. Maximum plasma concentration of rifapentine was lower, time to maximum plasma concentration (tmax) was greater, and elimination half-life (t 1/2) was longer in the patients with moderate-to-severe hepatic dysfunction than in those with mild-to-moderate dysfunction. However, mean area under the concentration-time curve extrapolated to infinity (AUC0-infinity) for the two groups was similar. AUC0-infinity values in patients with hepatic dysfunction were 19% to 25% higher than values previously reported for healthy volunteers. The 25-desacetyl metabolite appeared in plasma slowly after the single oral dose of rifapentine. Similar to findings for the parent drug, comparable plasma exposures of 25-desacetyl-rifapentine based on AUC0-infinity were found in the two groups of patients with mild-to-moderate and moderate-to-severe hepatic dysfunction. Rifapentine was well tolerated in this patient population, irrespective of the etiology or severity of hepatic dysfunction. These safety and pharmacokinetic results suggest that no dosage adjustments for rifapentine are needed in patients with hepatic impairment.

The effect of food on the bioavailability of dolasetron mesylate tablets.

Anzemet (dolasetron mesylate) is being developed for the prevention of chemotherapy-induced emesis and postoperative nausea and vomiting. Twenty-four healthy male subjects were orally dosed with dolasetron mesylate, 200 mg, after either an overnight fast or a high-fat breakfast. The ratio of the mean area under the plasma concentration-time curve of the reduced active metabolite (MDL 74,156) to infinity (AUC(0-infinity)) values in fed compared to fasting subjects was 86.3% with a 90% confidence interval for the ratio within (80, 125)%, indicating bioequivalence. The ratio of the mean MDL 74,156 maximum plasma concentration (Cmax) values was 70.6% in fed versus fasted subjects. The time to Cmax was statistically significantly longer after the high-fat breakfast (mean values, 1.11 h fasting and 1.80 h fed), probably due to delayed gastric emptying. It may be concluded that, although the rate of absorption was somewhat delayed, the extent of absorption did not change significantly when dolasetron mesylate was given with food.

Pharmacokinetics and safety of single intravenous and oral doses of dolasetron mesylate in healthy women.

Twenty-four healthy women received 2.4 mg kg-1 dolasetron mesylate (1.8 mg kg-1 dolasetron base) by a 10 min intravenous administration and by oral administration. Pharmacokinetics of dolasetron and of its active reduced metabolite MDL 74156 were monitored for 48 h in plasma. Urine was collected from 0 to 48 h, blood pressure and heart rate were measured at 0, 0.08, 1, 2, 12, 24, and 36 h, and ECGs were measured at 0, 0.08 (intravenous only), 1, 2, and 36 h after dosing. Dolasetron was widely distributed and rapidly reduced (mean t1/2 = 0.23 h) to MDL 74156 (mean t1/2 = 8.05 and 9.12 h after intravenous and oral administration respectively). MDL 74156 was extensively distributed; between 27 (oral route) and 33% (intravenous route) was eliminated unchanged in urine. Safety assessment showed mild to moderate headache, dizziness, and hot flushes after the intravenous administration and headache, abdominal cramps or pain, and constipation after oral administration. Small and clinically non-significant changes in PR, QRS, and QTc intervals were observed. We conclude that there is no obvious difference in dolasetron pharmacokinetics between healthy women and men and that dolasetron can be used as safely in women as in men.

Population pharmacokinetic modeling of isoniazid, rifampin, and pyrazinamide.

Isoniazid (INH), rifampin (RIF), and pyrazinamide (PZA) are the most important drugs for the treatment of tuberculosis (TB). The pharmacokinetics of all three drugs in the plasma of 24 healthy males were studied as part of a randomized cross-over phase I study of two dosage forms. Subjects ingested single doses of INH at 250 mg, RIF at 600 mg, and PZA at 1,500 mg. Plasma was collected for 36 h and was assayed by high-performance liquid chromatography. The data were analyzed by noncompartmental, iterative two-stage maximum a posteriori probability Bayesian (IT2B) and nonparametric expectation maximization (NPEM) population modeling methods. Fast and slow acetylators of INH had median peak concentrations in plasma (C[max]) of 2.44 and 3.64 microg/ml, respectively, both of which occurred at 1.0 h postdose (time of maximum concentrations of drugs in plasma [T(max)]), with median elimination half-lives (t1/2) of 1.2 and 3.3 h, respectively (by the NPEM method). RIF produced a median C(max) of 11.80 microg/ml, a T(max) of 1.0 h, and a t1/2 of 3.4 h. PZA produced a median C(max) of 28.80 microg/ml, a T(max) of 1.0 h, and a t1/2 of 10.0 h. The pharmacokinetic behaviors of INH, RIF, and PZA were well described by the three methods used. These models can serve as benchmarks for comparison with models for other populations, such as patients with TB or TB with AIDS.

Pharmacokinetics of the active metabolite (MDL 74,156) of dolasetron mesylate after oral or intravenous administration to anesthetized children.

BACKGROUND: Dolasetron mesylate is a selective 5-HT3 receptor antagonist under investigation as an antiemetic in children. Published studies indicate that its antiemetic activity results from the active metabolite (MDL 74,156), which is produced within 10 minutes of administration of dolasetron mesylate. METHODS: The pharmacokinetics of MDL 74,156 and the safety and tolerability of dolasetron mesylate were studied after a single oral or intravenous dose of 1.2 mg.kg-1 dolasetron mesylate to healthy children from 2 to 12 years of age. Oral dolasetron was administered to 12 children 1 to 2 hours before anesthesia. Intravenous dolasteron was administered to 18 children at induction of anesthesia. Serial blood samples were collected for 24 hours after dosing to measure the plasma concentration of MDL 74,156. Indexes of liver and kidney function were determined, and electrocardiograms and adverse events were recorded.

High-performance liquid chromatographic procedures for the quantitative determination of paclitaxel (Taxol) in human urine.

A reversed-phase high-performance liquid chromatographic (RP-HPLC) method has been developed and validated for the quantitative determination of paclitaxel in human urine. A comparison is made between solid-phase extraction (SPE) and liquid-liquid extraction (LLE) as sample pretreatment. The HPLC system consists of an APEX octyl analytical column and acetonitrile-methanol-0.2 microM ammonium acetate buffer pH 5 (4:1:5, v/v) as the mobile phase. Detection is performed by UV absorbance measurement at 227 nm. The SPE procedure involves extraction on Cyano Bond Elut columns. n-Butylchloride is the organic extraction fluid used for the LLE. The recoveries of paclitaxel in human urine are 79 and 75% for SPE and LLE, respectively. The accuracy for the LLE and SPE sample pretreatment procedures is 100.4 and 104.9%, respectively, at a 5 micrograms/ml drug concentration. The lower limit of quantitation is 0.01 microgram/ml for SPE and 0.25 microgram/ml for LLE. Stability data of paclitaxel in human urine are also presented.

Pharmacokinetics of paclitaxel and metabolites in a randomized comparative study in platinum-pretreated ovarian cancer patients.

PURPOSE: To investigate the pharmacokinetics and pharmacodynamics of paclitaxel in a randomized comparative study with four different treatment arms in patients with platinum-pretreated ovarian carcinoma. PATIENTS AND METHODS: Eighteen patients were entered onto this study in which paclitaxel was administered at a high dose of 175 mg/m2 versus a low dose of 135 mg/m2 on a 3- or 24-hour infusion schedule. A solid-phase extraction technique for sample pretreatment followed by a reverse-phase high-performance liquid chromatographic (HPLC) assay was used for analysis of plasma. RESULTS: Grade 3 neutropenia occurred in all four treatment arms. However, it was more severe on the 24-hour infusion schedule. Paclitaxel concentrations as low as 0.012 mumol/L were measured with the HPLC assay. With this low quantitation threshold, we found the plasma disappearance of paclitaxel to be triphasic, with half-lives t1/2(alpha), t1/2(beta), and t1/2(gamma) mean values for the different treatment arms of 0.19 hours (range, 0.01 to 0.4), 1.9 hours (range, 0.5 to 2.8), and 20.7 hours (range, 4 to 65), respectively. Eleven possible metabolites were found, of which three were identified as taxanes by on-line HPLC-photodiode array (PDA) detection. Investigation of pharmacodynamics shows no clear relationship between the pharmacokinetic parameters area under the plasma concentration time curve (AUC), area under the plasma concentration moment curve (AUMC), maximal plasma concentration (Cmax), clearance, and toxicity. However, a relationship was found between the duration of plasma concentrations above a threshold of 0.1 mumol/L with absolute neutrophil count (ANC) and white blood cell count (WBC). CONCLUSION: Paclitaxel is metabolized, and putative metabolic products can be found in plasma of patients treated with the drug. Our results indicate that myelosuppression can be predicted by the measurement of the duration of plasma concentrations above the threshold of 0.1 mumol/L.

Alpha-1 adrenergic coupling events induced by full and partial agonists in rabbit aorta.

Differences in the ability of full vs. partial agonists to initiate alpha-1 adrenergic receptor-mediated coupling events were studied in isolated segments of rabbit aorta. Mono- and dimethoxysubstituted tolazolines produced contractile responses which, at their maximum, were 27 to 100% of the response produced by the full agonist phenylephrine. In addition to differences in maximum response, contraction kinetics varied between full and partial agonists. Responses to partial agonists displayed a slower approach to peak tension and loss of the rapid phase of tension development which is associated with release of intracellular Ca++. Among the tolazoline series 3,5 dimethoxy-, 3 methoxy-, and 2 methoxy derivatives were compared further with phenylephrine for their ability to cause phosphatidylinositol cycle turnover, intracellular Ca++ release and Ca++ influx. For each of these coupling events, a rank of phenylephrine greater than or equal to 3, 5 greater than 3 greater than 2 was observed. However, a higher percentage of Ca++ influx vs. Ca++ release was observed for the partial agonists, suggesting that their contractile responses may be more dependent upon extracellular Ca++ than intracellular Ca++. Our results indicate that partial agonists initiate the same coupling events as full agonists; however, the relative proportion of Ca++ release and influx may be different for partial agonists because of the reduced rate of second messenger production.