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.

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.

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.

An investigation of the dose proportionality of deflazacort pharmacokinetics.

The dose proportionality of deflazacort was assessed following single-dose oral administration at doses of 3, 6, and 36 mg to 24 healthy young adult volunteers. The active metabolite of deflazacort (21-desacetyl deflazacort) was monitored in plasma using a sensitive, semi-microbore liquid chromatographic method. Cmax averaged 10.4 +/- 5.0, 19.8 +/- 7.5, and 132.6 +/- 52.5 ng mL-1 for the 3, 6, and 36 mg doses, respectively. AUC(0-infinity) averaged 38.5 +/- 37.1, 64.9 +/- 20.8, and 411.7 +/- 148.5 ng h mL-1 for the same three doses, respectively. Elimination half-life ranged from 1.9 +/- 0.5 h at the 6 mg dose to 2.4 +/- 1.5 h at the 36 mg dose. Regression analyses of dose versus Cmax and AUC(0-infinity) yielded intercepts which were not significantly different from zero (p > 0.05) and slopes which were significant (p < 0.05). Regression analysis of dose versus apparent oral clearance yielded a slope which was not significantly different from zero (p > 0.05). These data indicate that deflazacort exhibits dose-proportional pharmacokinetics.

Absence of food effects on the pharmacokinetics of terfenadine.

Administration of terfenadine (Seldane) immediately after a high fat breakfast slightly affects the rate but not the extent of absorption relative to fasting administration. Mean peak levels of the active metabolite were increased by 13 per cent but delayed by 0.9 h while AUC was virtually the same as when terfenadine was administered while fasting. Changes in rate of absorption may be due to delayed gastric emptying and more rapid terfenadine solubilization. In any case, these rate differences are unlikely to be clinically important in the absence of differences in extent of absorption.

Pharmacokinetics of terfenadine in healthy elderly subjects.

The pharmacokinetics of the terfenadine active metabolite, metabolite I, was examined in ten healthy elderly adults and ten younger adults after single-dose oral administration of 120-mg terfenadine. All subjects successfully completed the study without reporting sedation or other adverse events. Absorption was rapid in both the young and elderly. The mean Cmax was the same for both groups, 501 ng/mL, and occurred at 2.3 hours in the young subjects and 2.5 hours in elderly subjects. However, the apparent clearance was reduced by about 25% in the elderly. After correcting clearance for bodyweight, this difference was not statistically significant.

Pharmacokinetics and bioavailability of a new formulation of teicoplanin following intravenous and intramuscular administration to humans.

Pharmacokinetics, bioavailability, and local tolerance (at the site of intramuscular administration) of a new formulation of teicoplanin (400 mg/3 mL) were investigated in 24 normal, healthy, male volunteers. A single dose of 6 mg/kg was administered intravenously and intramuscularly using a randomized crossover design. Volunteers and investigator were blinded as to the route of administration; placebo was administered by the other route. Blood and urine samples were collected for 21 days and were analyzed for microbiological activity. The median (range) pharmacokinetic parameters of teicoplanin following single-dose iv administration were as follows: steady-state volume of distribution of 1.6 (1.2-2.8) L/kg; total clearance of 10.2 (8.6-15.1) mL/h/kg; renal clearance of 10.0 (7.9-13.8) mL/h/kg; and terminal disposition half-life of 168 (111-278) h. Following single-dose im administration, significantly more subjects complained of pain following administration of teicoplanin (58%) compared with placebo (4%). Teicoplanin was completely absorbed with a median (range) peak serum concentration of 12.3 (6.6-37.5) micrograms/mL occurring at a median (range) time of 4.1 (0.7-6.1) h. Since the 90% confidence interval for the ratio of areas under the serum concentration-time curve falls within the range of 80 to 120%, the extent of systemic absorption of teicoplanin following im administration is equivalent to that following iv administration.

Absence of effect of food on alprazolam absorption from sustained release tablets.

This study examined the effect of food on alprazolam absorption from a mixed polymeric matrix sustained release (SR) tablet in 21 healthy adults. Each subject received each of three treatments according to a crossover design: 1 mg alprazolam SR tablet while fasting; 1 mg alprazolam SR tablet immediately after a standardized breakfast; 1 mg alprazolam conventional tablet while fasting. The breakfast contained approximately 33 g protein, 55 g fat, and 58 g carbohydrate (850 calories). Serial blood samples were obtained and plasma alprazolam levels determined by HPLC. Results indicate that the SR tablet was minimally affected by food. Relative bioavailabilities of the SR tablet while fasting and with food were 100 per cent and 97 per cent, respectively. Although statistically significant, differences in mean Cmax values between SR tablets administered with and without food were small (12 per cent increase with food). Rates of absorption as measured by mean tmax values were also nearly the same: 7.2 h while fasting and 7.0 h with food. Absorption was relatively uniform with the SR tablets. Coefficients of variation for Cmax, tmax, and AUC were somewhat smaller with the SR tablet than with the conventional tablet.

Absorption kinetics of topical clindamycin preparations.

Systemic clindamycin absorption was examined in 12 male Caucasians without acne who received 1 ml of Cleocin-T and 1 ml of 1 per cent clindamycin HCl in Vehicle-N (Neutrogena) applied topically the face every 12 h for 4 days according to a crossover design. In a separate phase clindamycin phosphate was administered by an IV infusion of 300 mg over 10 min. Systemic absorption was much higher with clindamycin in Vehicle-N than with Cleocin-T. Absolute bioavailability calculated from cumulative urinary excretion and serum AUCs were in good agreement and averaged 1.7 per cent and 7.5 per cent for Cleocin-T and clindamycin in Vehicle-N, respectively. Peak serum concentrations ranged from less than 0.5 ng ml-1 to 6 ng ml-1 for Cleocin-T and from 4-20 ng ml-1 for clindamycin in Vehicle-N. Absorption profiles indicated zero order absorption with Cleocin-T. No appreciable systemic accumulation from the repeated topical applications was noted. Systemic exposure to clindamycin from these formulations is minimal.

Pharmacokinetics and pharmacodynamics of alprazolam following single and multiple oral doses of a sustained-release formulation.

The pharmacokinetics and pharmacodynamics of alprazolam after IV and oral sustained-release (SR) tablet administration were evaluated in 42 healthy, normal, male volunteers. All 42 subjects received a single 1-mg intravenous (IV) alprazolam dose. After a 1-week washout period, the subjects received one of three SR treatments as a single dose: one 1-mg SR tablet, three 1-mg SR tablets, or six 1-mg SR tablets. Beginning 2 days after single-dose SR treatment, each subject received the above SR doses for 3 days. The daily dose for the multiple-dose study was the same as the subject received in the single-dose study. Serial blood samples were collected after each treatment (single-dose IV, single-dose SR, and after the last SR multiple dose), and plasma samples were analyzed by high performance liquid chromatography. Sedation was assessed by a blinded observer at each blood sampling time. Mean pharmacokinetic parameters for IV administration were consistent with previous results. Pharmacokinetic parameters for the SR doses were consistent with linear kinetics over the dosage range studied. The mean absolute bioavailabilities of the SR tablets were greater than 0.84 after single SR doses. Maximal sedation was related to dose after single-dose SR administration. During multiple dosing, chronic tolerance was observed. Maximal sedation scores after 3 days of alprazolam SR administration were independent of the dose administered and were lower after multiple-dose administration than scores observed after single oral SR doses, although plasma alprazolam concentrations were at least 1.5 times higher with multiple dosing. Sedation data indicate that oral SR doses were well tolerated in multiple dosing.(ABSTRACT TRUNCATED AT 250 WORDS)

Absorption kinetics of rectally and orally administered ibuprofen.

The bioavailability of rectally administered sodium ibuprofen solution and aluminum ibuprofen suspension was determined in eight normal subjects relative to the same treatments administered orally. The results indicate that the suspension was less bioavailable than the solution irrespective of the route of administration. Although not bioequivalent, rectally administered ibuprofen solution compared favourably with orally administered ibuprofen solution. The mean AUC and Cmax from rectal administration were 87 per cent and 62 per cent of the corresponding values achieved after oral administration. Mean residence times and peak times were 1-3 h longer with the rectal solution, indicating a slower rate of absorption. Absorption after rectal administration was zero order in some subjects while absorption after oral administration was first order. This may be due to the large differences in surface area between absorption sites. Since sodium ibuprofen solution is absorbed when given rectally, this route of administration could be used in patients unable to take oral ibuprofen.

Absorption of minoxidil after topical application: effect of frequency and site of application.

The effect of application site and frequency on the systemic absorption of topical minoxidil was studied in 52 normal men. Subjects received 1 ml 3% minoxidil solution applied four, six, or eight times daily to the scalp or two, four, six, or eight times daily to the chest for 14 days. Serum and urine were collected and analyzed for minoxidil. No systemic minoxidil accumulation occurred from increasing application frequency to the scalp. Trends in the chest data suggest that absorption may have been lower with the twice-daily regimen. Absorption through the scalp and chest were similar for the lower-frequency regimens; however, trends in the eight-times-a-day regimens suggest that absorption may have been somewhat greater from application to the scalp. Systemic minoxidil accumulation resulting from frequent application is unlikely. The initial dose probably saturates the skin for a period of time longer than the dosing intervals examined.

Topical carbonic anhydrase inhibitors IV: Relationship between excised corneal permeability and pharmacokinetic factors.

Ethoxzolamide (1) and two analogues, representing a hydroxyethoxy and a hydrogen substitution on the 6-position of the benzene ring (2 and 3), were applied to rabbit eyes using a topical infusion method designed to provide a constant rate into aqueous humor. Statistical-moment theory was applied to the topical infusion data to describe disposition of each compound within the rabbit eye. For each analogue, it was possible to compare the corneal absorption rate constant (ka), aqueous humor elimination rate constant (k10), disposition mean residence time (MRTd), apparent steady-state volume of distribution (Vdss), and total ocular clearance (Qe). In vivo ocular ka values were related to maximum in vitro corneal penetration rates determined across excised rabbit corneas. In particular, 2 had a much longer residence time and a slower clearance than 1 and 3, which may be responsible for its ability to lower intraocular pressure when dosed topically to the rabbit eye, whereas 1 and 3 show no activity.

Topical carbonic anhydrase inhibitors. III: Optimization model for corneal penetration of ethoxzolamide analogues.

An analogue series representing modification to the benzene ring of ethoxzolamide has been evaluated for solubility, pKa, partitioning, and permeability across excised rabbit corneas. These physical parameters were correlated to Hammett sigma (para) and/or Hansch pi parameter values for each compound. From these correlations, a mathematical model was developed relating corneal permeability to molecular modifications of ethoxzolamide. A three-dimensional plot of maximum attainable penetration rate versus sigma (para) and pi yielded an optimal range of pi and sigma values from which an optimally penetrating analogue could be designed.

Ethoxzolamide analogue gel. A topical carbonic anhydrase inhibitor.

An analogue of ethoxzolamide, 6-hydroxyethoxzolamide, was synthesized to enhance corneal permeability yet retain carbonic anhydrase inhibitory activity for use in lowering intraocular pressure. In a 1% suspension, the analogue caused a small but statistically significant unilateral reduction of IOP when applied to one eye of normal rabbits. When formulated in a gel vehicle, 6-hydroxyethoxzolamide caused a more prolonged and larger reduction in IOP in normal and ocular hypertensive rabbits compared with its effect in suspension or with the parent compound.

Determination of ethoxzolamide in the iris/ciliary body of the rabbit eye by high-performance liquid chromatography: comparison of tissue levels following intravenous and topical administrations.

A specific high-performance liquid chromatographic method is described for ethoxzolamide following the extraction of the material from iris/ciliary body eye tissue in rabbits. The steps consist of base extraction and protein and enzyme deactivation, followed by acid treatment, extraction into ethyl acetate, evaporation, and solubilization with a 50% aqueous methanol solution. The samples were chromatographed on a reverse-phase phenyl column with a mobile phase consisting of 50% methanol in 1% acetic acid. The recovery was 74.3% over a 10-fold range of tissue concentrations. The sensitivity was 0.03 microgram/mL, and the response was linear over the concentration range (0.03-0.5 microgram/mL) used in the study. Intravenous (2.0- and 6.0-mg/kg) and topical (1% suspension) doses of ethoxzolamide were administered to rabbits. Iris/ciliary body tissues were excised 45 min after drug administration. The tissue levels after a dose of 6 mg/kg were statistically greater than the levels obtained after a dose of 2 mg/kg. The smaller intravenous dose represented the lowest dose for which a reduction in intraocular pressure could be measured. An initial transitory drop in intraocular pressure was detected for the topical dose. Iris/ciliary body levels in the treated eye could be detected for the 2-mg/kg iv and topical doses.