Pharmacokinetics of nevirapine and lamivudine in patients with HIV-1 infection.

The purpose of this parallel treatment group, double-blind, multicenter study was to characterize the pharmacokinetics of nevirapine and lamivudine when coadministered to patients with the HIV-1 infection. This pharmacokinetic interaction study was nested within a larger Phase III clinical trial conducted to characterize the safety and efficacy of coadministered nevirapine and lamivudine. One hundred HIV-1 infected patients with CD4+ lymphocyte counts < 200 cells/mm3and who were on a background of nucleoside (zidovudine [ZDV], didanosine [ddI], zalcitabine [ddC], stavudine [d4T]) therapy were randomly assigned to be treated with either nucleoside + lamivudine + nevirapine or nucleoside + lamivudine + placebo. Each patient underwent blood sampling at defined times for the purpose of determining the concentration of nevirapine in plasma and lamivudine in serum under steady-state conditions. Each patient was also monitored closely for concomitant administration of other drugs, including ZDV, ddI, ddC, d4T and cotrimoxazole. The pharmacokinetics of nevirapine and lamivudine were characterized using nonlinear mixed-effects modeling. There were no reported serious adverse events during the 40-day pharmacokinetic study. The results of the modeling analysis revealed that nevirapine had no effect on the pharmacokinetics of lamivudine. Estimates of the apparent clearance for nevirapine (CL/F = 3.3 L/hour; 95% confidence interval [CI] 2.9 to 3.7 L/hour) and lamivudine (CL/F 27.6 L/hour; 95% CI 22 to 33.2 L/hour) were consistent with the values reported in earlier trials. However, the results also showed that concomitant administration of lamivudine with cotrimoxazole resulted in a 31% reduction in the apparent clearance of lamivudine, resulting in a 43% increase in the average steady-state lamivudine serum concentrations. These results indicate that chronic concurrent administration of cotrimoxazole with lamivudine may significantly affect the steady-state pharmacokinetics of lamivudine.

Disposition and biotransformation of the antiretroviral drug nevirapine in humans.

The pharmacokinetics and biotransformation of the antiretroviral agent nevirapine (NVP) after autoinduction were characterized in eight healthy male volunteers. Subjects received 200-mg NVP tablets once daily for 2 weeks, followed by 200 mg twice daily for 2 weeks. Then they received a single oral dose (solution) of 50 mg containing 100 microCi of [(14)C]NVP. Biological fluids were analyzed for total radioactivity, parent compound (HPLC/UV), and metabolites (electrospray liquid chromatography/mass spectroscopy and liquid chromatography/tandem mass spectroscopy). Mean recovery of radioactivity was 91.4%, with 81.3% excreted in urine and 10.1% recovered in the feces over a period of 10 days. Circulating radioactivity was evenly distributed between whole blood and plasma. At maximum plasma concentration, parent compound accounted for approximately 75% of the circulating radioactivity. Mean plasma elimination half-lives for total radioactivity and NVP were 21.3 and 20.0 h, respectively. Several metabolites were identified in urine including 2-hydroxynevirapine glucuronide (18.6%), 3-hydroxynevirapine glucuronide (25.7%), 12-hydroxynevirapine glucuronide (23.7%), 8-hydroxynevirapine glucuronide (1.3%), 3-hydroxynevirapine (1.2%), 12-hydroxynevirapine (0.6%), and 4-carboxynevirapine (2.4%). Greater than 80% of the radioactivity in urine was made up of glucuronidated conjugates of hydroxylated metabolites of NVP. Thus, cytochrome P-450 metabolism, glucuronide conjugation, and urinary excretion of glucuronidated metabolites represent the primary route of NVP biotransformation and elimination in humans. Only a small fraction of the dose (2.7%) was excreted in urine as parent compound.

Antiviral effect and pharmacokinetic interaction between nevirapine and indinavir in persons infected with human immunodeficiency virus type 1.

Nevirapine and indinavir have the potential of affecting the pharmacokinetics of each other. In a prospective trial, 24 human immunodeficiency virus (HIV)-infected subjects on stable nucleoside or no therapy were treated with 800 mg of indinavir every 8 h. After 7 days, 200 mg of nevirapine a day was added for 14 days and then increased to 200 mg twice a day. At day 7 (before nevirapine), there was a sevenfold difference among the subjects in indinavir area under the curve (AUC), and there was a significant correlation between indinavir AUC (r2=0.378, P=.019), minimum plasma concentration (Cmin; r2=0.359, P=.023), maximum plasma concentration (Cmax; r2=0.340, P=.028), and plasma HIV RNA decline. Nevirapine significantly reduced median indinavir Cmin (47.5%) and AUC (27.4%) and, to a lesser extent, Cmax (11%). Plasma HIV RNA values were

Single dose pharmacokinetics and bioavailability of nevirapine in healthy volunteers.

The results of two randomized, single-dose, crossover bioavailability studies are presented which describe the pharmacokinetics and oral bioavailability of nevirapine, a novel nonnucleoside antiretroviral drug. In the first study 12 healthy male volunteers received nevirapine 15 mg via short-term i.v. infusion or orally as a 50 mg tablet or reference solution (50 mg/200 mL). Following the i.v. dose, nevirapine had a low systemic clearance (Mean +/- S.D., Cl = 1.4 +/- 0.3 L/h) and a prolonged elimination phase (t(1/2beta) = 52.8 +/- 14.8 h; MRT = 81.4 +/- 22.4 h). Nevirapine absolute bioavailability was 93 +/- 9% and 91 +/- 8% for the tablet and oral solution, respectively. In the second study, 24 healthy male volunteers were administered nevirapine as a 200 mg production-line tablet or oral reference solution (200 mg/200 mL). There was no significant difference in bioavailability between the tablet and reference solution. Overall, comparison of the pharmacokinetic parameters between the 50 and 200 mg doses indicates that nevirapine is well absorbed at clinically relevant doses. The absorption profiles using deconvolution revealed no evidence of differential enzyme induction between the two doses or routes of administration following a single dose.

Combination treatment with zidovudine, didanosine, and nevirapine in infants with human immunodeficiency virus type 1 infection.

BACKGROUND: In infants and children with maternally acquired human immunodeficiency virus type 1 (HIV-1) infection, treatment with a single antiretroviral agent has limited efficacy. We evaluated the safety and efficacy of a three-drug regimen in a small group of maternally infected infants. METHODS: Zidovudine, didanosine, and nevirapine were administered in combination orally to eight infants 2 to 16 months of age. The efficacy of antiretroviral treatment was evaluated by serial measurements of plasma HIV-1 RNA, quantitative plasma cultures, and quantitative cultures of peripheral-blood mononuclear cells. RESULTS: The three-drug regimen was well tolerated, without clinically important adverse events. Within four weeks, there were reductions in plasma levels of HIV-1 RNA of at least 96 percent (1.5 log) in seven of the eight study patients. Over the 6-month study period, replication of HIV-1 was controlled in two infants who began therapy at 2 1/2 months of age. Plasma RNA levels were reduced by 0.5 to 1.5 log in five of the other six infants. CONCLUSIONS: Although further observations are needed, it appears that in infants with maternally acquired HIV-1 infection, combined treatment with zidovudine, didanosine, and nevirapine is well tolerated and has sustained efficacy against HIV-1.

Pharmacokinetics, safety, and activity of nevirapine in human immunodeficiency virus type 1-infected children.

Phase I trials were conducted in human immunodeficiency virus type 1 (HIV-1)-infected children to examine the pharmacokinetics, safety, and antiretroviral activity of nevirapine, a nonnucleoside HIV-1 reverse transcriptase inhibitor. Nevirapine was rapidly absorbed, but the time to peak plasma concentrations increased with higher doses. Clearance was more rapid in chronic dosing studies than predicted by single-dose studies and was more rapid in younger children than in adolescent children. Rash, which occurred in 1 of the 21 study participants, was the single toxicity regarded as nevirapine-related. At doses > or = 240 mg/m2/day, 5 of 10 children experienced durable suppression of plasma p24 antigen to < 50% of baseline values through 8 weeks of nevirapine monotherapy. Viruses resistant to nevirapine were isolated from all children during therapy, but their isolation did not always predict loss of antiviral activity. The evaluation of nevirapine in combination therapy trials is underway in children.

Prediction of acetaminophen level from clinical history of overdose using a pharmacokinetic model.

A retrospective study was undertaken to determine the accuracy of predicting acetaminophen levels using the pharmacokinetic equation for first-order absorption and elimination of a single oral ingestion, (Formula: see text) Forty-four acute adult acetaminophen overdoses were studied during a 22-month period. Eighty levels drawn from 0 to 16 hours after ingestion were evaluated. To standardize the data, only first levels drawn in patients without prior spontaneous or ipecac-induced vomiting were analyzed (n = 26). Of these 26 levels, eight (31%) were drawn from 0 to two hours after ingestion, eight (31%) from two to four hours, and ten (38%) from four to 16 hours, with correlations of 0.59, 0.85, and 0.98, respectively. To determine the accuracy of predicting four-hour levels, five patients with first levels drawn at four hours, prior to vomiting, were evaluated. Substituting appropriate constants, the condensed equation, Cp4h = (0.59) (mg/kg dose), was used to predict the four-hour level (r = 0.99). Preliminary data suggest the ability to accurately predict four-hour acetaminophen levels from ingestion history alone using pharmacokinetic equations.

Antibiotic-resistant group JK bacteria in hospitals.

The organisms designated as Center for Disease Control group JK are gram-positive rods that have previously been described as causing serious infection in compromised hosts. Four years of hospital experience with this group of organisms in Clinical Center patients was reviewed. Studies were also undertaken on specific wards to determine frequency of occurrence and distribution patterns. Inguinal cultures taken on two wards showed that 30 to 35% of patients were colonized with group JK and that newly admitted patients may already be colonized at the time of admission. Colonization was shown to persist for weeks and sometimes months. Isolates obtained throughout the hospital were predominantly from cancer patients, particularly in wounds, abscesses, and drainage sites. Most blood isolates were from granulocytopenic patients with hematological malignancies.

Surveillance of nosocomial infections by antibiotic monitoring.

Records of all patients receiving intravenous gentamicin sulfate during a 92-day interval were reviewed to detect nosocomial infections that had been missed by routine surveillance. Only 46 of 48 of the 99 treatment courses had been detected. In 96% of cases not detected by routine surveillance, use of gentamicin was considered justified. Of the patients missed by surveillance, 83% were in oncology wards, and 46% had severe neutropenia and fever of unknown origin. Antibiotic surveillance proved a useful adjunct in estimating the incidence of nosocomial infections in such patients.

Technetium-99m-human serum albumin: evaluation of a commercially produced kit.

Results are reported on the use of a commercial kit for the labeling of human serum albumin with 99mTc. One-hour blood levels obtained in 20 subjects undergoing gated cardiac imaging were found to be 46.0 +/- 10.5% (s.d.) of the administered dose. The highest labeling efficiencies (94.2 +/- 9.3%) were obtained when human serum albumin 25% (salt-poor) was used. Satisfactory nuclear cardiac ventriculographic images were obtained in patients receiving the radiopharmaceutical when the labeling efficiency was at least 85%. Occasional batches were milky in appearance, contained black particulate matter, were acidic, or contained a high percentage of unbound 99mTc activity. Although this kit makes 99mTc-human serum albumin accessible to most nuclear medicine facilities for general clinical use, an active quality control program is required prior to use in patients.

Generator-produced 99m TcO4-: carrier free.

A solution of 99m-TCO4-minus, as eluted from a 99Mo-99mTc radionuclide generator contains a greater chemical quantity of technetium than that attributable to the metastable isomer alone. The isomeric transition of the radionuclide of interest, 99mTc, gives rise to a determinable and chemically significant quantity of technetium carrier, 99Tc. A method is presented for calculating the total chemical quantity of technetium in a generator eluate.