Albert Dorr

Single‐Dose Pharmacokinetics of Valganciclovir in HIV‐ and CMV‐Seropositive Subjects

As a result of the low oral bioavailability of ganciclovir, a prodrug was developed to improve the bioavailability of ganciclovir. This study was designed to investigate the fasting, single‐dose pharmacokinetics as well as the absolute and relative bioavailability of a valine ester prodrug of ganciclovir, valganciclovir, as compared to oral and intravenous ganciclovir in asymptomatic HIV+ and CMV+ subjects. In this open‐label, randomized, three‐period crossover study, 18 subjects received, in random order, single oral doses of valganciclovir 360 mg and ganciclovir 1000 mg and an intravenous infusion of ganciclovir 5 mg/kg over 1 hour. Valganciclovir was rapidly and extensively hydrolyzed to ganciclovir, resulting in significantly greater bioavailability compared to 1000 mg oral ganciclovir (60.9% vs. 5.6%, respectively). Higher peak serum concentrations were reached earlier following valganciclovir (ganciclovir [2.98 ± 0.77 μg/mL at 1.0 ± 0.3 h]) than following oral ganciclovir (0.47 ± 0.17 μg/mL and 2.2 ± 1.0 h). Mean total ganciclovir AUCs following oral ganciclovir (1000 mg) and 360 mg valganciclovir (3.8 ± 1.2 and 10.8 ± 1.9 μg‐h/mL) were less than that following a standard 5 mg/kg intravenous infusion of ganciclovir (25.1 ± 3.8 μg‐h/mL). In summary, valganciclovir is a prodrug with a favorable safety profile with enhanced bioavailability and significantly higher serum concentrations of ganciclovir than following oral administration of ganciclovir itself.

The Pharmacokinetics and Tolerability of the Oral Neuraminidase Inhibitor Oseltamivir (Ro 64–0796/GS4104) in Healthy Adult and Elderly Volunteers

The tolerability and pharmacokinetics of Ro 64–0802, a potent, selective inhibitor of influenza neuraminidase, and its oral prodrug oseltamivir were investigated in three double‐blind, placebo‐controlled studies. Two studies involved healthy adult volunteers (18–55 years) (n = 48) who received single (20–1000 mg) or bid doses (50–500 mg) (n = 32) of oseltamivir or placebo for 7 days. Healthy elderly volunteers (≥65 years) (n = 24) received oseltamivir 100 to 200 mg bid or placebo for 7 days in a third study. Measurable plasma concentrations of the active metabolite appeared rapidly in plasma and were significantly higher and longer lasting than those of oseltamivir. Pharmacokinetics of both compounds were linear. Multiple‐dose exposure was predictable from single‐dose data, and steady‐state plasma concentrations were achieved within 3 days of bid drug administration. Oseltamivir was well tolerated at single doses of up to 1000 mg and twice‐daily doses of up to 500 mg. Adverse events were mild in intensity. Exposure to both prodrug and active metabolite was increased in elderly patients by approximately 25%. However, due to the wide safety margin of both compounds, no dose adjustment is necessary for elderly patients.

Pharmacokinetics of plasma enfuvirtide after subcutaneous administration to patientswith human immunodeficiency virus: Inverse Gaussian density absorption and 2-compartment disposition*

Enfuvirtide (T‐20) is the first of a novel class of human immunodeficiency virus (HIV) drugs that block gp41‐mediated viral fusion to host cells. The objectives of this study were to develop a structural pharmacokinetic model that would adequately characterize the absorption and disposition of enfuvirtide pharmacokinetics after both intravenous and subcutaneous administration and to evaluate the dose proportionality of enfuvirtide pharmacokinetic parameters at a subcutaneous dose higher than that currently used in phase III studies.

Pharmacokinetics of anti-influenza prodrug oseltamivir in children aged 1–5 years

ObjectiveThe prodrug oseltamivir has been shown to be efficacious and safe for the treatment of influenza for patients 1xa0year of age or older; however, pharmacokinetic information was lacking for children below 5xa0years of age. This study was conducted to assess the metabolic and excretory capacity of oseltamivir and its active carboxylate metabolite in young children.MethodsTwelve healthy children aged 1–5xa0years received a single oral suspension dose of oseltamivir (45xa0mg for 3–5xa0years, 30xa0mg for 1–2xa0years). Plasma and urine concentrations of oseltamivir and the carboxylate were determined by means of liquid chromatography/tandem mass spectrometry.ResultsMean peak plasma concentration and area under the plasma concentration–time curve values normalized to milligram per kilogram oseltamivir dose in the 1- to 2-year group are lower than those in the 3- to 5-year group. Mean body weight normalized oral clearance of oseltamivir and its carboxylate in younger subjects aged 1–2xa0years (259xa0ml/min/kg and 12.2xa0ml/min/kg) were, respectively, 52% and 30% higher than those in older subjects aged 3–5xa0years (170xa0ml/min/kg and 9.4xa0ml/min/kg).ConclusionThe results demonstrate that infants as young as 1xa0year old can metabolize and excrete oseltamivir efficiently. The data derived from this study provide the starting dose of oseltamivir for further investigation in an efficacy study among influenza-infected infants less than 1xa0year of age.

Pharmacokinetics and Dosage Recommendations for an Oseltamivir Oral Suspension for the Treatment of Influenza in Children

AbstractObjective: Oseltamivir (Ro 64-0796) is an ester prodrug of the active metabolite Ro 64-0802 (oseltamivir carboxylate), a potent and selective inhibitor of the neuraminidase enzyme of influenza virus. In this study we report the pharmacokinetics of oseltamivir in healthy children volunteers (study 1) and in children with influenza (study 2).n Study Participants and Methods: In study 1, an open-label, single dose study, serial plasma samples were obtained from a total of 18 healthy children (5 to 18 years) who were grouped by age (n = 6 per group) and received single oral doses of oseltamivir 2 mg/kg. In study 2, a randomised, placebo controlled phase III study in paediatric children (1 to 12 years) presenting with influenza symptoms, 199 pharmacokinetic sparse samples were obtained from 87 patients, and serial samples were obtained from 5 patients. Pooled data were compared with those from adult studies.n Results: Children (1 to 12 years) eliminated the active metabolite faster than both adolescents (13 to 18 years) and adults, resulting in lower exposure to the active drug. In these children, oseltamivir 2 mg/kg twice daily resulted in drug exposures within the range associated with tolerability and efficacy in adults administered approximately 1 mg/kg twice daily. Unit doses of oseltamivir 30, 45 and 60mg oral suspension are recommended twice daily in children weighing ≤15kg (or ≤331b, aged 1 to 3 years), >15 to 23kg (or >33 to 511b, aged 4 to 7 years) and >23 to 40kg (or >51 to 881b, aged 8 to 12 years), respectively. A 75mg capsule may be a viable dosage formulation in children (e.g. over 8 years of age) who are able to swallow solid dosage forms.n Conclusions: Young children cleared the active metabolite oseltamivir carboxylate at a faster rate than older children and adults. Convenient administration recommendations for the oseltamivir oral suspension in children are possible to maintain drug exposure within the target window.

Lack of Enzyme‐Inducing Effect of Rifampicin on the Pharmacokinetics of Enfuvirtide

The primary objective was to determine whether rifampicin influences the pharmacokinetics of enfuvirtide in HIV‐1‐infected patients. In a single‐center, open‐label, one‐sequence crossover, clinical pharmacology study, 12 HIV‐1‐infected adults received enfuvirtide (90 mg, twice daily) on days 1 to 3 and days 11 to 13 (morning dose only on days 3 and 13) and rifampicin (600 mg, once daily) from days 4 to 13. Plasma concentrations were measured for enfuvirtide and its metabolite (days 3 and 13) and rifampicin (day 13 only). The ratios of least squares means (LSM) and 90% confidence intervals for enfuvirtide and enfuvirtide metabolite pharmacokinetic parameters (AUC12h, Cmax, Ctrough) were estimated in the presence and absence of rifampicin. Treatments were compared using an analysis of variance for natural log‐transformed variables, with factors patient and treatment. Efficacy and safety were also monitored. Steady‐state rifampicin had no appreciable effect on any of the pharmacokinetic parameters assessed for either enfuvirtide or its metabolite. The ratio of LSM for AUC12h, Cmax, and Ctrough for enfuvirtide was 97.5%, 103%, and 84.9%, respectively, and 108%, 112%, and 92.9%, for the enfuvirtide metabolite. Rifampicin did not affect the t1/2 of enfuvirtide or its metabolite. There were no unexpected effects of rifampicin on the short‐term antiviral effect or safety of the administered antiretroviral treatment. The pharmacokinetics of enfuvirtide are not induced by a 10‐day pretreatment with rifampicin.

Assessment of drug-drug interaction potential of enfuvirtide in human immunodeficiency virus type 1-infected patients

Enfuvirtide is the first drug to block human immunodeficiency virus type 1 (HIV‐1) glycoprotein 41–mediated viral fusion to host cells. This study investigated whether enfuvirtide can influence the activities of cytochrome P450 (CYP) enzymes in HIV‐1–infected patients.

Influence of subcutaneous injection site on the steady-state pharmacokinetics of enfuvirtide (T-20) in HIV-1-infected patients

BACKGROUNDnEnfuvirtide is the first in a new class of antiretrovirals (ARVs), the fusion inhibitors, and the first ARV to be administered by subcutaneous (s.c.) injection.nnnOBJECTIVESnThe primary objective of this study was to determine the steady-state pharmacokinetics and relative bioavailability of enfuvirtide following sc injection at three separate anatomical sites: abdomen (A), thigh (B) and arm (C).nnnSTUDY DESIGNnA single-center, open-label, multiple-dose, three-way randomized, crossover study. Twelve HIV-1-infected adults were recruited from three ongoing Phase II enfuvirtide clinical trials and randomized into three groups. Each group continued to receive s.c. injection of enfuvirtide, at a dose of 90 mg twice daily (bid), according to one of three treatment sequences: ABC, BCA or CAB; over three consecutive periods of approximately 7 days each. Plasma concentrations of enfuvirtide and its metabolite (Ro 50-6343) were measured using a validated liquid chromatography-tandem mass spectrometry method.nnnRESULTSnThe relative bioavailability of enfuvirtide, based on AUC12h and abdomen as a reference site, was 101% for thigh and 117% for arm. The AUC12h of Ro 50-6343 ranged from 14 to 16% of that for enfuvirtide. Although injection site reactions (ISRs) were common, the overall grading (based on pain or discomfort) of all reported ISRs was Grade 1 (mild). The incidence of ISRs varied according to the site of injection, as did the signs and symptoms associated with them. No patient required treatment for an ISR.nnnCONCLUSIONSnComparability among the three injection sites, in terms of both absorption and the ISR profile, allows HIV-1-infected patients the freedom to choose and to rotate, if necessary, the site of enfuvirtide injection among the three anatomical sites.

Pharmacokinetics, Safety, and Tolerability of R411, a Dual α4β1-α4β7 Integrin Antagonist After Oral Administration at Single and Multiple Once-Daily Ascending Doses in Healthy Volunteers

R411 is a dual α4β1‐α4β7 integrin antagonist under development for the treatment of chronic asthma. The objective of this study was to investigate the pharmacokinetics and safety of R411 and its active metabolite, RO0270608, in humans. A 3‐part phase I trial was conducted in 132 healthy volunteers: (1) 12 subjects received 200 mg R411 as a single oral dose or 100 mg RO0270608 as an intravenous infusion in a 1‐sequence crossover design; (2) 7 groups of 10 subjects received 1 of 7 single oral doses of R411 (10–1200 mg) in a parallel, placebo‐controlled, ascending adaptive dose design; and (3) 5 groups of 10 subjects each received repeated oral qd doses of R411 (50–900 mg) for up to 3 weeks in a parallel, placebo‐controlled, ascending adaptive dose design. The absolute bioavailability of RO0270608 (mean ± standard deviation) after oral administration of R411 was 27% ± 4%, and the terminal half‐life was 7.33 ± 2.29 hours. After IV infusion of RO0270608, total clearance (mean ± standard deviation) was 19.4 ± 7.1 L/h, and the volume of distribution was 93.1 ± 36.1 L. After single ascending oral doses of R411, area under the concentration‐time curve from 0 to infinity of active metabolite RO0270608 increased proportionally from 150 to 1200 mg (P < .05). Following repeated administration, the oral clearance was independent of time. No drug accumulation was observed, and no safety concerns were revealed up to a dose of 900 mg after up to 3 weeks of treatment.

Lack of Pharmacokinetic Interaction between the Oral Anti-Influenza Prodrug Oseltamivir and Aspirin

ABSTRACT Twelve volunteers completed a two-sequence, three-way crossover study of a single 900-mg aspirin dose and multiple doses of 75 mg of oseltamivir in the absence and presence of 900 mg of aspirin. The plasma and urine results demonstrated no pharmacokinetic interaction between oseltamivir and aspirin.