An open-label clinical trial of the effects of age and gender on the pharmacodynamics, pharmacokinetics and safety of the ghrelin receptor agonist anamorelin.

PURPOSE: To assess the effect of age and gender on the pharmacokinetics (PK) of the ghrelin receptor agonist anamorelin. METHODS: Three demographic cohorts of healthy subjects were enrolled in this single-center, open-label study. Subjects received a single oral dose (25 mg) of anamorelin HCl. Serial blood samples were collected over 24 hours to assess anamorelin PK and circulating growth hormone (GH) levels. Data were compared with a reference cohort. RESULTS: Anamorelin was rapidly absorbed in all cohorts; peak concentrations were observed 30-45 minutes and 2-4 hours post-dose, which declined biexponentially with mean terminal half-lives of 6-7 hours. An age effect on Cmax and AUC∞ was not apparent; however, mean AUC∞ values were approximately 1.8-1.9-fold higher in the female cohorts than in the reference male cohort. GH increase was rapid and virtually identical in both sexes, though attenuated in elderly subjects. No clinically significant safety or tolerability findings were observed. CONCLUSIONS: While PK parameters do suggest higher exposure in females, this effect is considered to be modest given the variability of the 6-8 subjects per cohort. Moreover, no such effect was observed in the pharmacodynamic responses, thus, dose adjustment for age and gender is considered unnecessary.

Pharmacokinetics of oral recombinant human parathyroid hormone [rhPTH(1-31)NH2] in postmenopausal women with osteoporosis.

BACKGROUND AND OBJECTIVES: Teriparatide [rhPTH(1-34)OH] is a subcutaneously administered bone anabolic drug that increases bone mineral density (BMD) and reduces the risk of osteoporotic fracture. Because rhPTH(1-34)OH is administered by injection, oral delivery is a desirable alternative. However, the peroral delivery of peptides is challenging due to their susceptibility to protease digestion and low permeability through the intestinal layers. The objective of this study was to assess the pharmacokinetics of a PTH analog (rhPTH(1-31)NH2) in a novel oral tablet formulation and to compare them to subcutaneously administered teriparatide in postmenopausal osteoporotic women in a phase 2 proof-of-concept clinical study. METHODS: This was a 24-week repeat-dose, randomized, double blind, parallel group phase 2 study with three once-daily treatment arms: oral rhPTH(1-31)NH2 tablets (5 mg), matching placebo tablets, and open-label teriparatide (20 µg daily subcutaneous injection). The primary endpoint of this study was to assess the change in lumbar spine BMD of orally administered rhPTH(1-31)NH2 tablets compared to baseline. This study was conducted at three sites in Denmark and at one site in Estonia. The patients included were women diagnosed with postmenopausal osteoporosis as detected by lumbar spine dual-energy X-ray absorptiometry, with exclusion of those with prior treatment with bone-active agents. The study treatment consisted of orally formulated recombinant human PTH(1-31)NH2, placebo, or subcutaneous teriparatide as an active comparator. RESULTS: The pharmacokinetic profile at first and last dose was evaluated and correlated with the primary endpoint, which was to characterize the percent change from baseline in BMD of the lumbar spine after 24 weeks of once daily treatment with rhPTH(1-31)NH2. The pharmacokinetic profile for the tablets showed a pulsatile peak with durations of at least 1 h but less than 5 h, which is consistent with the requirement for bone anabolic activity. The mean maximum (peak) plasma drug concentration (C max) values for patients receiving tablets at week 0 (n = 32) and week 24 (n = 28) were 295 and 207 pg/mL, respectively. The mean time to reach maximum (peak) plasma concentration following drug administration (t max) for both week 0 and week 24 was 3.25 h. The mean area under the concentration-time curve (AUC) for week 0 and week 24 was 178 and 141 pg·h/mL, respectively. No significant differences were observed between weeks 0 and 24 in any pharmacokinetic parameters tested, demonstrating good reproducibility, no time-dependent changes, and little or no accumulation of the study drug. The systemic exposure as measured by C max values was higher for the oral tablets formulation than for subcutaneous teriparatide. CONCLUSIONS: The observed data demonstrate that the enteric-coated tablet formulation technology was able to generate consistently robust and pulsatile levels of exposure of rhPTH(1-31)NH2. There was no apparent correlation between higher exposures and adverse events, even though the pharmacokinetic variability was somewhat higher with the tablets. These positive results recommend this orally delivered drug candidate for further clinical development.

The pharmacokinetics of toborinone in subjects with congestive heart failure and concomitant renal impairment and/or concomitant hepatic impairment.

The pharmacokinetics of toborinone was studied in subjects with congestive heart failure (CHF) and concomitant renal and/or hepatic disease. At the time of admission, subjects were grouped based on estimated creatinine clearance and serum bilirubin. Glomerular filtration rate was assessed using iothalamate clearance. Hepatic function was assessed using the caffeine metabolism test and indocyanine green clearance. No significant differences were observed in mean toborinone pharmacokinetic parameters among the four study groups. Positive correlations were observed between toborinone clearance and the measured indices of renal and hepatic function: creatinine clearance, iothalamate renal clearance, paraxanthine/caffeine ratio, and indocyanine green clearance. Toborinone clearance decreased with decreasing creatinine clearance, decreasing glomerular filtration rate, decreasing demethylation metabolic activity, and decreasing hepatic bloodflow, although no significant differences were observed in any mean toborinone pharmacokinetic parameters evaluated among the four study groups.

The effects of concomitant administration of theophylline and toborinone on the pharmacokinetics of both compounds in poor and extensive metabolizers via CYP2D6.

This study investigated the effects of the concomitant administration of theophylline and toborinone on the pharmacokinetics of both compounds in poor and extensive metabolizers via CYP2D6. In period 1, a single dose of 3.5 mg/kg theophylline was administered orally. In period 2, a single dose of 1.0 microg/kg/min toborinone was infused over 6 hours. In period 3, 3.5 mg/kg theophylline was coadministered with 1.0 microg/kg/min toborinone. Serial blood and pooled urine samples were collected before and after toborinone administration for the quantification of toborinone and its metabolites in plasma and urine. Serial blood samples were collected before and after theophylline administration for the quantification of theophylline and its metabolites in plasma. No significant differences were observed in toborinone pharmacokinetics between poor and extensive metabolizers via CYP2D6. Toborinone coadministration with theophylline did not result in a substantive effect on the disposition of theophylline and vice versa.