David M. Tenero

Steady‐State Pharmacokinetics of Carvedilol and Its Enantiomers in Patients with Congestive Heart Failure

Carvedilol is a relatively new drug with β‐and α1‐receptor blocking activity and antioxidant effects recently approved for the treatment of congestive heart failure (CHF). An ascending, multiple‐dose study was completed in 20 male patients with stable New York Heart Association (NYHA) Class III or IV CHF. The pharmacokinetics of carvedilol, S(−)‐carvedilol, R(+)‐carvedilol, and the active metabolites of carvedilol was assessed at steady state after twice‐daily oral administration of carvedilol for 7 days at 6.25, 12.5, 25, and 50 mg doses. Carvedilol exhibited stereoselective pharmacokinetics in CHF patients with dose‐proportional increases in steady‐state plasma concentrations of carvedilol and its enantiomers. Mean AUC and Cmax values for carvedilol were up to twofold higher in patients with Class IV CHF as compared to those with Class III CHF. Steady‐state plasma concentrations of the active metabolites also increased in a dose‐proportional manner and were typically 10% or less of that observed for carvedilol. In general, carvedilol was adequately tolerated by adult male CHF patients at the dose levels (6.25–50 mg) evaluated in this study as adverse events were consistent with those frequently observed in patients with CHF.

Pharmacokinetics and Protein Binding of Eprosartan in Healthy Volunteers and in Patients with Varying Degrees of Renal Impairment

This was an open‐label, parallel group study to compare the pharmacokinetics of multiple oral doses of eprosartan in subjects with normal renal function (Clcr >80 mL/min; n = 8) and patients with mild (Clcr 60–80 mL/min; n = 8), moderate (Clcr 30–59 mL/min; n = 15), or severe (Clcr <30 mL/min; n = 3) renal insufficiency. Each subject received oral eprosartan 200 mg twice daily for 6 days and a single dose on day 7. Mean total maximum concentration (Cmax) and area under the concentration—time curve from 0 to 12 hours (AUC0–12) were similar for healthy subjects and those with mild renal impairment, but were an average of 25% to 35% and 51% to 55% greater for patients with moderate and severe renal impairment, respectively, compared with healthy subjects. Mean renal clearance (Clr), which was similar for healthy subjects and patients with mild renal impairment, was decreased an average of 41% and 95% in the groups with moderate and severe renal impairment, respectively, compared with normal subjects. Eprosartan was highly bound to plasma proteins in all groups; however, the unbound fraction was increased approximately two‐fold in the group with severe renal impairment. Mean unbound Cmax and AUC0–12 were an average of 53% to 61% and 185% to 210% greater for the patients with moderate and severe renal impairment, respectively, compared with healthy subjects. Headache was the most common adverse experience reported in all subgroups. Eprosartan was safe and well tolerated regardless of degree of renal impairment. Cmax and AUC were increased and renal clearance decreased in patients with moderate to severe renal impairment in comparison to healthy subjects and patients with mild renal impairment. However, based on the moderate renal clearance and known safety profile of eprosartan, it is not necessary to adjust the dose of eprosartan in patients with renal insufficiency.

Pharmacokinetics of intravenously and orally administered eprosartan in healthy males: absolute bioavailability and effect of food

Eighteen healthy males received a single 300 mg oral dose of eprosartan as the commercial wet granulation formulation under fasting conditions and following a high‐fat breakfast and a single 20 mg intravenous (i.v.) dose. The pharmacokinetics of i.v. eprosartan (mean±S.D.) were characterized by a low systemic plasma clearance (131.8±36.2 mL min−1) and a small steady‐state volume of distribution (12.6±2.6 L). Oral bioavailability averaged 13.1%, due to incomplete absorption. In vitro dynamic flow cell dissolution data showed that pH‐dependent aqueous solubility of eprosartan is one factor which limits absorption. Eprosartan terminal half‐life was shorter after i.v. (approximately 2 h) versus oral (approximately 5–7 h) administration, which may be due to detection of an additional elimination phase or absorption rate‐limited elimination following oral administration. Oral administration of eprosartan following a high‐fat meal compared with fasting conditions resulted in a similar extent of absorption (based on AUC), but a decreased absorption rate. Cmax was approximately 25% lower, and a median delay of 1.25 h in time to Cmax was observed when eprosartan was administered with food. These minor changes in exposure are unlikely to be of clinical consequence; therefore, eprosartan may be administered without regard to meal times.

A dose proportionality study of eprosartan in healthy male volunteers.

The present study investigated the proportionality of exposure after single oral doses of 100, 200, 400, and 800 mg of eprosartan, a nonpeptide, nonbiphenyl angiotensin II receptor antagonist, in 23 healthy young men. Eprosartan was safe and well tolerated. Exposure to eprosartan increased with dose but in a less than proportional manner. For each two‐fold dose increase, area under the concentration—time curve (AUC) increased an average of 1.6 to 1.8 times and maximum plasma drug concentration (Cmax) increased an average of 1.5 to 1.8 times. For both parameters, the greatest difference from the dose multiple was observed between the 400‐ and 800‐mg doses. Dose proportionality of eprosartan, as assessed by an equivalence‐type approach using the 100‐mg dose as the reference and a 30% acceptance region (0.70, 1.43), was achieved for the 200‐ and 400‐mg doses for AUC and the 200‐mg dose for Cmax. The observed changes in the pharmacokinetics of eprosartan suggest slight saturation of absorption of eprosartan over the 100‐ to 800‐mg dose range, most likely due to the physicochemical properties of the drug (pH‐dependent aqueous solubility and lipophilicity).

Pharmacokinetics of Eprosartan in Healthy Subjects, Patients with Hypertension, and Special Populations

After oral administration of eprosartan to healthy volunteers, bioavailability is approximately 13%, with peak plasma concentrations occurring 1–2 hours after an oral dose in the fasted state. Food slows the rate of absorption and changes the overall extent by less than 25%, which is unlikely to be of clinical consequence. Plasma concentrations increase in a slightly less than dose‐proportional manner from 100–800 mg. There is no evidence of significant accumulation of eprosartan with long‐term therapy. The drugs terminal elimination half‐life is typically 5–9 hours after oral administration. The agent is highly protein bound (∼ 98%), with low plasma clearance (∼ 130 ml/minute) and small volume of distribution (∼ 13 L). It is primarily unmetabolized by the liver, with less than 2% of an oral dose recovered in the urine as a glucuronide. Biliary (primary) and renal excretion contribute to its elimination. No dosage adjustment is required in patients with mild to moderate renal impairment. Although an increase in systemic exposure to eprosartan was observed in the elderly, in patients with hepatic impairment, and in those with severe renal disease, this finding is unlikely to be of clinical consequence, based on the drugs excellent safety and tolerability profile (doses up to 1200 mg) in phase III clinical trials in hypertensive patients. Eprosartan can be safely administered to these special populations without an initial dosage adjustment, with subsequent dosing individualized based on tolerability and response.

Pharmacokinetics and Protein Binding of Eprosartan in Hemodialysis-Dependent Patients with End-Stage Renal Disease

Study Objectives. To compare eprosartan pharmacokinetics in hemodialysis patients and in volunteers with normal renal function, and to determine the effect of hemodialysis on these values.

Population pharmacokinetics of S(−)-carvedilol in healthy volunteers after administration of the immediate-release (IR) and the new controlled-release (CR) dosage forms of the racemate

Carvedilol is a β1-, β1-, and α1-adrenoreceptor blocker indicated for treatment of hypertension and mild-tosevere congestive heart failure. The objective of this study was to develop and evaluate a single population model that describesS(−)-carvedilol pharmacokinetics from both the immediate-release (IR) and the new controlled-release dosage forms of the racemate. Carvedilol IR data (1270 measurements) were obtained from 2 open-label studies (50 mg/25 mg Q12 hours for 2 doses). Carvedilol CR data (2058 measurements) were obtained from an open-label, nonrandomized, dose-rising (10, 20, 40, and 80 mg), 4-period balanced crossover study. All data were simultaneously analyzed using NONMEM V. Leverage analysis and internal evaluations were conducted for the final model. A 2-compartment model with first-order absorption and elimination provided the best fit. The model included different absorption rates (KAs) for the CR and IR morning (IRAM) and evening (IRPM) doses; incorporating change-points at certain times. Estimates of KAs indicated that the absorption was slower at equivalent times and extended for CR relative to IR carvedilol. Oral clearance ofS(−)-carvedilol was 149 L/h. The IRPM and the CR doses had bioavailability (Frel) of 0.80 and 0.76, respectively, relative to the IRAM dose. The inter-subject variability in KAs was lower for the CR dosage form than the original IR dosage form. Estimation of interoccasion variability on KAs and Frel for the CR dosage form improved the fit. The model performed well in simulation and leverage analysis indicated its robustness. The model will be a useful tool for future simulation studies.

Effect of hepatic disease on the pharmacokinetics and plasma protein binding of eprosartan.

Study Objective. To evaluate the pharmacokinetics and plasma protein binding of eprosartan in hepatic disease.

Disposition and Metabolism of GSK2251052 in Humans: A Novel Boron-Containing Antibiotic

(S)-3-(Aminomethyl)-7-(3-hydroxypropoxy)-1-hydroxy-1,3-dihydro-2,1-benzoxaborole (GSK2251052) is a novel boron-containing antibiotic that inhibits bacterial leucyl tRNA synthetase, and that has been in development for the treatment of serious Gram-negative infections. In this study, six healthy adult male subjects received a single i.v. dose of [14C]GSK2251052, 1500 mg infused over 1 hour. Blood, urine, and feces were collected over an extended period of 14 days, and accelerator mass spectrometry was used to quantify low levels of radioactivity in plasma at later time points to supplement the less-sensitive liquid scintillation counting technique. An excellent mass balance recovery was achieved representing a mean total of 98.2% of the dose, including 90.5% recovered in the urine. Pharmacokinetic analysis demonstrated that radioactivity was moderately associated with the blood cellular components, and together with GSK2251052, both were highly distributed into tissues. The parent compound had a much shorter half-life than total radioactivity in plasma, approximately 11.6 hours compared with 96 hours. GSK2251052 and its major metabolite M3, which resulted from oxidation of the propanol side chain to the corresponding carboxylic acid, comprised the majority of the plasma radioactivity, 37 and 53% of the area under the plasma versus time concentration curve from time zero to infinity, respectively. Additionally, M3 was eliminated renally, and was demonstrated to be responsible for the long plasma radioactivity elimination half-life. A combination of in vitro metabolism experiments and a pharmacokinetic study in monkeys with the inhibitor 4-methylpyrazole provided strong evidence that alcohol dehydrogenase, potentially in association with aldehyde dehydrogenase, is the primary enzyme involved in the formation of the M3 metabolite.

Intrapulmonary pharmacokinetics of GSK2251052 in Healthy Volunteers

ABSTRACT The plasma and intrapulmonary pharmacokinetics (PK) of intravenous (i.v.) GSK2251052, a novel boron-containing antimicrobial, were evaluated in healthy adult subjects. Thirty subjects underwent bronchoscopy and timed bronchoalveolar lavage (BAL) either following a single dose (cohort 1) or after 5 twice-daily doses (cohort 2) of 1,500 mg GSK2251052 i.v. Serial PK and safety assessments were obtained throughout the study. Bronchoscopy was performed on a single occasion in each subject at 2, 6, or 12 h after start of infusion. Noncompartmental analysis was performed to calculate PK parameters. Thirty subjects completed the study. The mean clearance (CL), volume of distribution at steady state (Vss), and half-life (t1/2) values were 22 liters/h, 231 liters, and 10.7 h, respectively. Approximately 30% of the dose was excreted unchanged in urine. The GSK2251052 concentrations in epithelial lining fluid (ELF) and alveolar macrophages (AM) were approximately 50% and 500 to 600%, respectively, compared to the concentration in plasma. the GSK2251052 exposures in ELF and AM were comparable following single- and repeat-dose administration. The most frequently reported drug-related adverse event (AE) was mild to moderate infusion site reactions (7 subjects) that occurred primarily in the repeat-dose cohort. No serious drug-related AEs or clinically significant trends in laboratory values, vital signs, or electrocardiograms were observed. GSK2251052 given as a 1,500-mg infusion was generally tolerated following single- or repeat-dose administration. GSK2251052 distributes into both the ELF and AM of healthy volunteers, which supports further study in patients with pneumonia.