Elizabeth K. Hussey

Pharmacokinetics, absolute bioavailability, and absorption characteristics of lamivudine.

Lamivudine is a novel cytosine nucleoside analog, reverse transcriptase inhibitor that has shown activity against human immunodeficiency virus (HIV) types 1 and 2 and hepatitis B virus in vitro. This study was conducted to compare the absolute bioavailability, pharmacokinetics, and absorption characteristics of oral solution, 100‐mg capsule, and 100‐mg tablet formulations of lamivudine with those of intravenous lamivudine. Twelve patients with HIV were enrolled in a single‐center, randomized, open‐label, four‐way crossover study. Treatment arms consisted of 100 mg intravenous lamivudine (administered over 1 hour), 100 mg oral lamivudine (1 mg/mL), a 100‐mg capsule, and a 100‐mg tablet, each followed by a 3‐ to 14‐day washout period. Serial blood samples over 24 hours were obtained after each dose administration. Serum concentration data were analyzed to determine pharmacokinetic parameter estimates including area under the curve (AUC), terminal half‐life (t1/2), mean residence time (MRT) for each formulation, systemic clearance, oral clearance, and apparent volume of distribution (Vd). Absolute bioavailability and in vivo mean absorption time (MAT) and mean dissolution time (MDT) were calculated for the oral formulations. Deconvolution techniques were used to calculate the input rate for the oral solution, capsule, and tablet. The two one‐sided t test was used to determine bioequivalency among oral formulations with respect to logarithmic transformed estimates of AUC and maximum peak concentration (Cmax). Mean (CV) systemic clearance and Vd 22 after intravenous administration of lamivudine were 22.6 L/h (15%) and 99 L (28%), respectively; mean t1/2 ranged from 8.41 to 9.11 hours for all formulations; and MRT ranged from 4.42 to 5.77 hours for all formulations. Mean absolute bioavailability ranged from 86% to 88% for the oral solution, capsule, and tablet. All oral formulations were considered bioequivalent for AUC and Cmax. The MAT was 1.32 hour for the oral solution, and MDT was 0.03 and −0.11 hours for the capsule and oral solution, respectively. The oral formulations of lamivudine examined in this study demonstrated acceptable bioavailability for oral administration. The solid oral formulations (capsule and tablet) show rapid dissolution properties with an absorption rate similar to or exceeding those observed with the oral solution. This suggests that dissolution is not an important factor for the rate of absorption of lamivudine. The use of deconvolution techniques using PCDCON provides valuable insight into the absorption characteristics of lamivudine.

Effects of the Neuraminidase Inhibitor Zanamivir on Otologic Manifestations of Experimental Human Influenza

Middle ear pressure (MEP) abnormalities are frequently observed during influenza virus infection and may serve as surrogate markers for the risk of otitis media. MEP abnormalities were evaluated in adult volunteers who were inoculated with influenza A/Texas/36/91(H1N1) or B/Yamagata/88 virus and given the antiviral zanamivir (GG167) intranasally as prophylaxis or early treatment in randomized, double-blind, placebo-controlled trials. In the influenza A prophylaxis studies, 15% of 61 zanamivir recipients versus 61% of 33 placebo recipients showed significant MEP abnormalities (P < .01). In the influenza A early treatment trial, 32% of 31 infected zanamivir recipients versus 73% of 26 infected placebo recipients developed MEP abnormalities (P < .01). In the influenza B prophylaxis trial, 16% of 25 zanamivir versus 44% of 9 placebo recipients showed abnormalities (P = .09). These findings indicate that the neuraminidase inhibitor zanamivir, which is effective in reducing experimental influenza illness, provides protection against the development of MEP abnormalities.

Single‐Dose Pharmacokinetics and Pharmacodynamics of Sergliflozin Etabonate, a Novel Inhibitor of Glucose Reabsorption, in Healthy Volunteers and Patients With Type 2 Diabetes Mellitus

Sergliflozin, the active entity of sergliflozin etabonate, is a selective inhibitor of sodium‐dependent glucose cotransporter 2 (SGLT2). The pharmacokinetics and pharmacodynamics of sergliflozin were evaluated following single oral dose administration of sergliflozin etabonate (5–500 mg) in healthy volunteers (n = 22) and patients with type 2 diabetes mellitus (n = 8). The prodrug was rapidly and extensively converted to sergliflozin; the latter displayed linear kinetics, reached maximum plasma concentrations at ∼30 to 45 minutes postdose (tmax), and had a plasma elimination half‐life (t1/2) of ∼0.5 to 1 hour. Both prodrug and active entity showed low glomerular filtration and/or extensive renal tubular reabsorption, with <0.5% of the administered dose being recovered in the urine. In both populations, sergliflozin etabonate produced a dose‐related glucosuria under fasting conditions and following glucose loading but did not appreciably affect urinary electrolyte excretion or fluid balance. The magnitude and duration of the glucosuric effect closely paralleled plasma sergliflozin concentrations. Sergliflozin did not significantly affect fasting plasma glucose levels but produced transient attenuation of the plasma glucose AUC following glucose challenge. Single doses of sergliflozin etabonate 5 to 500 mg were well tolerated, and there were no clinically significant adverse laboratory findings.

Remogliflozin etabonate, a selective inhibitor of the sodium‐dependent transporter 2 reduces serum glucose in type 2 diabetes mellitus patients

Aims: Remogliflozin etabonate (RE) is the pro‐drug of remogliflozin (R), a selective inhibitor of renal sodium‐dependent glucose transporter 2 (SGLT2) that improves glucose control via enhanced urinary glucose excretion (UGE). This study evaluated the safety, tolerability, pharmacokinetics and pharmacodynamics of repeated doses of RE in subjects with type 2 diabetes mellitus (T2DM).

Multiple‐Dose Pharmacokinetics and Pharmacodynamics of Sergliflozin Etabonate, a Novel Inhibitor of Glucose Reabsorption, in Healthy Overweight and Obese Subjects: A Randomized Double‐Blind Study

Sergliflozin, the active entity of sergliflozin etabonate, is a selective inhibitor of the sodium‐dependent glucose cotransporter‐2 in the renal tubule. The pharmacokinetics and pharmacodynamics of sergliflozin were examined during administration of sergliflozin etabonate (500 or 1000 mg) or placebo 3 times daily (tid) for 14 days in healthy overweight or obese human volunteers (n = 18). At the doses tested, sergliflozin showed less than dose‐proportional pharmacokinetic characteristics. Mean half‐life of the active entity was approximately 2 hours; there was no evidence of drug accumulation. Sergliflozin etabonate produced rapid and sustained suppression of renal glucose reabsorption, resulting in a dose‐related glucosuria, and a transient increase in urinary electrolyte and fluid loss; plasma glucose, insulin, and electrolyte levels were unchanged. Sergliflozin etabonate produced a rapid, dose‐related reduction in body weight (mean changes of −0.09, −1.55, and −1.74 kg from baseline to day 15 with placebo, sergliflozin etabonate 500 mg, and sergliflozin etabonate 1000 mg, respectively), apparently through increased urinary calorie loss rather than through osmotic diuresis. Sergliflozin etabonate 500 or 1000 mg tid was generally well tolerated; no clinically significant adverse events were identified. Renal function (creatinine clearance) was not affected by sergliflozin etabonate, although urinary microalbumin, N‐acetyl‐beta‐D‐glucosaminidase, and β2‐microglobulin levels tended to increase.

Sumatriptan absorption from different regions of the human gastrointestinal tract.

Sumatriptan exhibits low oral bioavailability partly due to presystemic metabolism, which may vary with regional differences in metabolic activity throughout the gastrointestinal tract. This study evaluated sumatriptan absorption in humans after administration orally and by oroenteric tube into the jejunum and cecum. Because the site of cecal administration varied, pharmacokinetic parameters for sumatriptan and its major metabolite were compared statistically only after oral and jejunal administration. One-half of the oral dose was recovered in the urine as parent (3%) and metabolite (46%). Sumatriptan was absorbed throughout the gastrointestinal tract; absorption was similar after oral and jejunal administration, and less after cecal administration. The metabolite AUC and the AUC ratio (metabolite/parent) were significantly lower after jejunal compared to oral administration; the AUC ratio was two-fold lower after cecal administration. Results suggest that presystemic metabolism of sumatriptan varies throughout the gastrointestinal tract and/or regional differences exist in the absorption of metabolite formed within the gastrointestinal tract.

Remogliflozin Etabonate, a Selective Inhibitor of the Sodium-Glucose Transporter 2, Improves Serum Glucose Profiles in Type 1 Diabetes

OBJECTIVE Remogliflozin etabonate (RE), an inhibitor of the sodium-glucose transporter 2, improves glucose profiles in type 2 diabetes. This study assessed safety, tolerability, pharmacokinetics, and pharmacodynamics of RE in subjects with type 1 diabetes. RESEARCH DESIGN AND METHODS Ten subjects managed with continuous subcutaneous insulin infusion were enrolled. In addition to basal insulin, subjects received five randomized treatments: placebo, prandial insulin, 50 mg RE, 150 mg RE, and mg RE 500. RESULTS Adverse events and incidence of hypoglycemia with RE did not differ from placebo and prandial insulin groups. RE significantly increased urine glucose excretion and reduced the rise in plasma glucose concentration after oral glucose. RE reduced incremental adjusted weighted mean glucose (0–4 h) values by 42–49 mg/dL and mean glucose (0–10 h) by 52–69 mg/dL. CONCLUSIONS RE can be safely administered with insulin in type 1 diabetes and reduces plasma glucose concentrations compared with placebo.

Interspecies Scaling and Pharmacokinetic Parameters of 3TC in Humans

3TC is a dideoxy‐nucleoside analogue that has demonstrated in‐vitro activity against human immunodeficiency virus (HIV). 3TC concentrations in humans were predicted before the initiation of clinical trials by interspecies scaling of pharmacokinetic parameters observed in animal species. Clearance and volume of distribution were estimated for humans using linear regression on a log‐log scale of each parameter versus body weight for rats and dogs. The concentration‐time profile and the average serum concentration at steady state after various dosage regimens were estimated as a basis for initial dose selection for clinical trials. The predicted parameters (clearance of 16.3 L/hr and volume of distribution of 40 L for a 70‐kg man) were compared with that observed (mean clearance of 24 L/hr and mean volume of distribution of 96 L, mean weight of 74 kg) in 20 asymptomatic, HIV positive, volunteers after single intravenous doses of 3TC. Interspecies scaling was applied prospectively as a rationale for dose selection of 3TC in clinical trials.

A population pharmacokinetic analysis of zanamivir in subjects with experimental and naturally occurring influenza: effects of formulation and route of administration.

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.

Pharmacokinetics and tolerability of a single inhaled dose of zanamivir in children

Abstract Objective The purpose of this study was to examine the pharmacokinetics, safety, and tolerability of zanamivir in children. Background Zanamivir is a potent inhibitor of viral neuraminidase that is effective against both influenza A and B infections. Methods A pediatric study was conducted to examine the pharmacokinetics, safety, and tolerability of zanamivir in children who had signs of respiratory illness. Twenty-four children aged 3 months to 12 years received zanamivir administered as a single, orally inhaled, 10-mg dose either by nebulizer (in patients ® (in patients ≥5 years of age). Serum and urine zanamivir concentrations were analyzed both before dosing and from 0.5 to 8 hours after dosing. Results The rate and extent of absorption of zanamivir were independent of the inhalation formulation or of the patients age. Median maximum serum concentrations were 47 ng/mL in younger patients (aged ≥3 months to Conclusions Results of the present study suggest that a 10-mg dose of zanamivir is safe and well tolerated when used in children who have signs and symptoms of respiratory illness.