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Fostemsavir, a prodrug of the first‐in‐class HIV‐1 attachment inhibitor temsavir, is approved for the treatment of multidrug‐resistant HIV‐1 in adults; its use in pediatric populations is currently being studied. Population pharmacokinetic modeling across pediatric weight bands was used to guide pediatric fostemsavir dose selection. Dosing simulations demonstrated that twice‐daily fostemsavir 600‐mg (adult dose) and 400‐mg doses met safety and efficacy criteria for 35 kg or greater and 20 or greater to less than 35 kg pediatric weight bands, respectively. Temsavir relative bioavailability of 2 low‐dose fostemsavir extended‐release formulations (3 × 200 mg; formulations A and B) and reference formulation (600 mg extended release) was assessed in a 2‐part, open‐label, randomized, crossover study in healthy adults. Part 1 (N= 32) compared single‐dose temsavir relative bioavailability, and Part 2 (N= 16) evaluated the impact of fed versus fasted conditions using the selected low‐dose formulation. Temsavir geometric mean ratios for the area under the plasma concentration–time curve from time zero to infinity and maximum concentration for formulation B were bioequivalent to the reference formulation. Temsavir maximum concentration for formulation B was similar in fed and fasted states, but area under the plasma concentration–time curve from time zero to infinity geometric mean ratio was increased under fed conditions, consistent with previous results in adults. These analyses demonstrated efficient pediatric dose selection using a model‐based approach.

Staphylococcus aureusbacteraemia is a common cause of severe community-acquired and hospital-acquired infection worldwide. We tested the hypothesis that adjunctive rifampicin would reduce bacteriologically confirmed treatment failure or disease recurrence, or death, by enhancing early S aureuskilling, sterilising infected foci and blood faster, and reducing risks of dissemination and metastatic infection.

Drug development at different stages may require assessment of similarity of pharmacokinetics (PK). The common approach for such assessment when the difference is drug formulation is bioequivalence (BE), which employs a hypothesis test based on the evaluation of a 90% confidence interval for the ratio of average pharmacokinetic (PK) parameters. The role of formulation effect in BE assessment is replaced by subject population in PK similarity assessment. The traditional approach for BE requires that the PK parameters, primarily AUC and Cmax, be obtained from every individual. Unfortunately in many clinical circumstances, some or even all of the individuals may be sparsely sampled, making the individual evaluation difficult. In such cases, using models, particularly population models, becomes appealing. However, conducting an appropriate statistical test based on population modeling in a form consistent, at least in principle, with traditional 90% confidence interval approach is not so straightforward as it may appear. This manuscript proposes one such approach that can be applied to sparse sampling situations. The approach aims to maintain, as much as possible, the appropriateness of the hypothesis test. It is applied to data from clinical studies to address a need in drug development for assessment of PK similarity in different populations.

The aim of the current study was to characterize the pharmacokinetics of GW420867X, a new nonnucleoside reverse transcriptase inhibitor, using a single escalating dose protocol in healthy volunteers. Four dose levels were investigated in sequential order: 300, 600, 900, and 1200 mg, with a ratio of 4:1 subjects receiving active or placebo treatment, respectively. Following single‐dose administration, GW420867X was readily absorbed with a median time to peak concentration of 3 to 5 hours. GW420867X plasma exposure (AUC) was dose proportional but variable within the 300 to 1200 mg dose range. Less than dose‐proportional increases were observed for Cmax. The terminal elimination t1/2was 50 hours, which supports once‐daily dosing in future studies. Plasma trough concentrations of GW420867X at 24 hours after dosing were many fold greater than the in vitro IC50HIV‐1HXB2in MT4 cells. GW420867X was generally well tolerated following single‐dose administration up to 900 mg; increased central nervous system‐related adverse events were observed at higher doses. GW420867X had a favorable pharmacokinetic and safety profile that would enable this drug to be explored in future clinical studies with HIV‐1 infected patients at doses that would provide appropriate safety and efficacy.

A phase I, repeat‐dose, open‐label study was conducted to determine the pharmacokinetics and safety of zidovudine and lamivudine, coadministered orally every 12 hours, in 16 neonates whose mothers were infected with human immunodeficiency virus type 1 (HIV‐1). The prospective mothers had been stabilized on a zidovudine/lamivudine regimen since week 36 of pregnancy to prevent mother‐to‐child transmission of HIV During 1 week postpartum, the mothers received zidovudine 300 mg plus lamivudine 150 mg every 12 hours and breastfed. Neonatal treatment was initiated 12 hours following birth with 4 mg/kg of zidovudine suspension plus 2 mg/kg of lamivudine solution every 12 hours; this regimen was continued for 1 week. Between days 1 and 7 of neonatal treatment, the neonatal oral clearance (CL/F) of zidovudine and lamivudine increased by 2‐fold (p < 0.001) and 1.6‐fold (p = 0.004), respectively, possibly reflecting maturation of intestinal hepatic and renal function occurring during the first week of life. Day 7/day 1 ratios for exposure (area under the serum concentration‐time curve [AUC]) and maximum observed serum concentration (Cmax) were 0.48 and 0.63, respectively, for zidovudine and 0.64 and 0.73, respectively, for lamivudine. At the time of delivery, the geometric mean cord/maternal concentration ratio was 1.24 for zidovudine and 1.12 for lamivudine, indicating free passage of each drug across the placenta. The maternal and neonatal treatment regimens were well tolerated. The results of this study confirm that in the neonate, a convenient regimen combining zidovudine 4 mg/kg and lamivudine 2 mg/kg, administered orally every 12 hours, provides zidovudine serum exposure very similar to that reported with the standard neonatal zidovudine regimen of 2 mg/kg every 6 hours, as well as lamivudine serum exposure within the range reported in adults receiving lamivudine 15 0mg twice a day and children receiving 4 mg/kg twice a day.

The effect of food on the bioavailability of GW420867X, a novel nonnucleoside reverse transcriptase inhibitor, was investigated in 15 young, healthy, male volunteers. A single oral dose of GW420867×100 mg was administered in the fasted state, after a high‐fat meal, and after a meal of normal fat composition. Tolerability and pharmacokinetic sampling were assessed at baseline and up to 600 hours. The median concentration‐time plots for each treatment group were essentially superimposable. Neither the rate nor the extent of absorption of GW420867X was significantly affected by food. The median time to peak plasma concentration was 3 to 4 hours, irrespective of treatment. Pairwise comparisons using the fasted treatment as the comparator showed no impact of food on GW420867X pharmacokinetics. GW420867X was well tolerated. There were no serious or treatment‐limiting adverse events; all episodes reported were rated as mild to moderate. The bioavailability of GW420867X was unaffected by food. GW420867X may be administered independently of food and fat intake.

The objective of this study was to determine the metabolic profile, routes of elimination, and total recovery of amprenavir and its metabolites after a single oral dose of [14C]‐amprenavir. Six healthy male subjects each received a single oral 630 mg dose of amprenavir containing 95.76 μCi of [14C]‐amprenavir in this Phase I mass balance study. The metabolic disposition of amprenavir was determined through analyses of radiocarbon in whole blood, plasma, urine, and stool samples, collected for a period of 10 to 17 days postdosing. Cerebral spinal fluid (CSF) sampling was conducted on day 1. The ratio of unchanged amprenavir AUC0→∞ to plasma radiocarbon was 27%, suggesting that most of the radiocarbon was metabolites. The median total recovery of the administered dose of radiocarbon was 89% (range: 66%‐93%), with 75% (range: 56%‐80%) recovered in the feces and 14% (range: 10%‐17%) in the urine. Most of the recovered radiocarbon in the feces and urine was excreted within 240 and 48 hours postdose, respectively. Of the 75% of the radiocarbon dose recovered in the feces, 62% wasidentified as a metabolite resulting from dioxidation of the tetrahydrofuran ring (GW549445X) and 32% as a metabolite resulting from subsequent oxidation of the p‐aniline sulfonate group (GW549444X). Unchanged amprenavir was below the limit of quantitation in feces and urine. Therefore, approximately 94% of the dose excreted in the feces was accounted for by these two metabolites. Concentrations of radiocarbon in the CSF were below the limit of quantitation in 5 of 6 subjects sampled. In summary, oral amprenavir is extensively metabolized in humans, with concentrations of unchanged drug below the limits of quantitation in urine and feces. The majority (75%) of administered radiocarbon was excreted in feces.

Nucleoside analogs (zidovudine, didanosine, zalcitabine, stavudine, abacavir, lamivudine) have been administered as antiretroviral agents for more than a decade. They undergo anabolic phosphorylation by intracellular kinases to form triphosphates, which inhibit human immunodeficiency virus replication by competitively inhibiting viral reverse transcriptase. Numerous methods are used to elucidate the intracellular metabolic pathways of these agents. Intracellular and extracellular factors affect intracellular phosphorylation. Lack of standardization and complexity of methods used to study phosphorylation in patients limit interpretation of study results and comparability of findings across studies. However, in vitro and in vivo studies give important insights into mechanisms of action, metabolic feedback mechanisms, antiviral effects, and mechanisms of toxicity, and have influenced dosing regimens of nucleoside analogs.

The pharmacokinetics of zanamivir were evaluated in subjects from three phase I single‐center and two phase II multicenter, randomized, double‐blind, multidose, placebo‐controlled trials. A total of 96 phase I subjects received zanamivir (3.6 to 16 mg) intranasally two or six times daily for 4 to 5 days beginning 4 hours before or 1 to 2 days after inoculation with influenza virus. A total of 75 phase II subjects with influenza or a history of exposure to naturally occurring influenza virus were administered zanamivir as an intranasal spray (3.4 mg/nostril), inhaled powder (10 mg), or combination of intranasal and inhaled formulations twice daily for 5 days. Population parameters (including demographic factors, zanamivir formulation, infection‐related variables, and concurrent medication use) were estimated by a nonlinear mixed‐effect modeling software program (NONMEM) using a one‐compartment model with first‐order absorption and conditional estimation algorithm. Formulation and route of administration were the most significant factors affecting the pharmacokinetics of zanamivir. Relative bioavailability of the inhaled powder to the intranasal drops and spray was 2.3 and 1.6, respectively. No significant differences in pharmacokinetic parameters were observed when demographic variables, indices of infection, or concurrent medication use were considered in either phase I or phase II population analyses.

A single‐center, open‐label, three‐way crossover study was conducted in 24 healthy subjects to assess (1) the bioequivalence of a combined lamivudine 150 mg/zidovudine 300 mg tablet relative to the separate brand‐name components administered concurrently and (2) the effect of food on the bioavailability of the drugs from the combination tablet. The subjects were randomly assigned to receive each of the following three treatments, separated by a 5‐ to 7‐day washout period: one lamivudine/zidovudine combination tablet after an overnight fast, one lamivudine 150 mg tablet and one zidovudine 300 mg tablet simultaneously after an overnight fast, or one lamivudine/zidovudine combination tablet 5 minutes after completing a standardized high‐fat breakfast (67 g fat, 58 g carbohydrate, and 33 g protein). Serial blood samples were collected up to 24 hours postdose for the determination of lamivudine and zidovudine plasma concentrations. Standard pharmacokinetic parameters were estimated. Treatments were considered bioequivalent if 90% confidence intervals for the ratio of least squares (LS) means for the lamivudine and zidovudine area under the plasma concentration‐time curve (AUC∞) and maximum observed plasma concentration (Cmax) fell entirely within 0.80 to 1.25 for log‐transformed parameters. The combined lamivudine/zidovudine tablet was bioequivalent in the extent (AUC∞) and rate of absorption (Cmaxand time of Cmax[tmax]) to the individual brand‐name drug components administered concurrently under fasted conditions. Geometric LS mean ratios and 90% confidence intervals for AUC∞and Cmaxwere 0.97 (0.92, 1.03) and 0.94 (0.84, 1.06), respectively, for lamivudine and 0.99 (0.91, 1.07) and 0.97 (0.82, 1.15), respectively, for zidovudine. The extent of absorption of lamivudine and zidovudine from the combination tablet was not altered by administration with meals, indicating that this formulation may be administered with or without food. However, food slowed the rate of absorption, delayed the tmax, and reduced the Cmaxof lamivudine and zidovudine. These changes were not considered clinically important. All formulations were well tolerated under fasted and fed conditions.

ABSTRACTLamivudine population pharmacokinetics were investigated by using nonlinear mixed-effect modelling (NONMEM) analysis of data from 394 human immunodeficiency virus (HIV)-infected patients treated with lamivudine (150 to 300 mg every 12 h) in two large, phase III clinical efficacy-safety trials, NUCA3001 and NUCA3002. Analyses of 1,477 serum lamivudine concentration determinations showed that population estimates for lamivudine oral clearance (CL/F; 25.1 liters/h) and volume of distribution (V/F; 128 liters) were similar to values previously reported for HIV-infected patients in phase I pharmacokinetic studies. Lamivudine CL/F was significantly influenced by the covariates creatinine clearance and weight and not affected by age, Centers for Disease Control and Prevention (CDC) classification, CD4+cell count, HIV type 1 (HIV-1) RNA PCR, or gender and race when CL/F was corrected for differences in patient weight. The population estimate for lamivudine V/F was not significantly influenced by the covariates gender, race, age, weight, renal function, HIV-1 RNA PCR, or CDC classification and CD4+cell count when creatinine clearance was included with CL/F in the model. Lamivudine disposition was significantly influenced by renal function. However, as only three patients had an estimated creatinine clearance of <60 ml/min, dosage adjustments for patients with impaired renal function should not be determined based on the population parameters derived in this analysis.

Heat treatment of patient samples is utilized as a method to decrease the risk of accidental transmission of human immunodeficiency virus (HIV). Heat treatment has been reported to affect the outcome of drug analysis. In this study, the effects of heat treatment (56°C for 5 h) and storage for 2 months at - 20°C on the stability of trimethoprim (TMP) and sulfamethoxazole (SMX) at three different concentrations in serum (10/100, 1/20, and 0.1/5 μg/mL) each were evaluated. Simultaneous determination of TMP, SMX, and sulfamethazine (SMeth), the internal standard, in serum was performed by a reversed-phase high-performance liquid chromatographic (HPLC) procedure with isocratic elution and ultraviolet detection. The peak/height ratios (PHRs) for each sample from untreated and heat-treated groups were compared. No statistically significant differences were found between untreated and heat-treated groups for TMP. Heat treatment decreased the PHR for SMX at 100 μg/ml concentration (p = 0.042) and increased the PHR for SMX at 20 μg/ml concentration (p = 0.049). These marginal differences are unlikely to be significant. Storage of samples for 2 months at −20°C had no statistically significant effect on sample PHRs. Thus, heat treatment of serum does not alter clinical interpretation of TMP and SMX at clinically relevant concentrations and may protect laboratory workers from accidental HIV exposure.

Objective: To determine the effect of multiple dosing of combined sulfamethoxazole and trimethoprim on the single-dose pharmacokinetics of lamivudine.Methods: Fourteen subjects with human immunodeficiency virus who had CD4+ cells ≥200/mm3received two single doses of 300 mg lamivudine, separated by 7 to 14 days, in a randomized two-way crossover study. Treatment consisted of lamivudine alone versus trimethoprim-sulfamethoxazole (160/800 mg) daily on days 1 through 4 followed by lamivudine plus trimethoprim-sulfamethoxazole on day 5. Blood and urine were collected over 24 to 32 hours to determine lamivudine, trimethoprim, sulfamethoxazole, and N-4-acetylsulfamethoxazole concentrations.Results: Coadministration of a single dose of lamivudine and trimethoprim-sulfamethoxazole after daily dosing for 5 days altered the pharmacokinetics of lamivudine. A 43% increase in area under the concentration-time curve (AUC∞) and a 35% decrease in renal clearance (CLR) were observed when lamivudine was coadministered with trimethoprim-sulfamethoxazole compared with lamivudine alone. The geometric least-squares mean (95% confidence intervals) for the parameters of lamivudine alone and when given concurrently with trimethoprim-sulfamethoxazole were as follows: AUC∞, 10,124 (9,432–10,866) and 14,448 (13,461–15,508) ng · hr/ml, respectively; CLR, 16.6 (14.1–19.4) and 10.8 (9.5–12.6) L/hr, respectively. Coadministration did not significantly alter the pharmacokinetics of trimethoprim or sulfamethoxazole.Conclusions: Coadministration of lamivudine with trimethoprim-sulfamethoxazole resulted in an increased AUC∞and a decreased CLRof lamivudine. However, given the favorable safety profile of lamivudine, it is unlikely that this interaction will result in a significant increase in concentration-related toxicity at the doses studied.