Stacy Dilzer

Pharmacokinetics and Pharmacodynamic Effects of the Oral DPP-4 Inhibitor Sitagliptin in Middle-Aged Obese Subjects

Sitagliptin (MK‐0431) is an oral, potent, and selective dipeptidyl peptidase‐IV (DPP‐4) inhibitor developed for the treatment of type 2 diabetes. This multicenter, randomized, double‐blind, placebo‐controlled study examined the pharmacokinetic and pharmacodynamic effects of sitagliptin in obese subjects. Middle‐aged (45–63 years), nondiabetic, obese (body mass index: 30–40 kg/m2) men and women were randomized to sitagliptin 200 mg bid (n = 24) or placebo (n = 8) for 28 days. Steady‐state plasma concentrations of sitagliptin were achieved within 2 days of starting treatment, and >90% of the dose was excreted unchanged in urine. Sitagliptin treatment led to ∼90% inhibition of plasma DPP‐4 activity, increased active glucagon‐like peptide‐1 (GLP‐1) levels by 2.7‐fold (P < .001), and decreased post—oral glucose tolerance test glucose excursion by 35% (P < .050) compared to placebo. In nondiabetic obese subjects, treatment with sitagliptin 200 mg bid was generally well tolerated without associated hypoglycemia and led to maximal inhibition of plasma DPP‐4 activity, increased active GLP‐1, and reduced glycemic excursion.

Metabolism And Excretion of the Dipeptidyl Peptidase 4 Inhibitor [14C]Sitagliptin in Humans

The metabolism and excretion of [14C]sitagliptin, an orally active, potent and selective dipeptidyl peptidase 4 inhibitor, were investigated in humans after a single oral dose of 83 mg/193 μCi. Urine, feces, and plasma were collected at regular intervals for up to 7 days. The primary route of excretion of radioactivity was via the kidneys, with a mean value of 87% of the administered dose recovered in urine. Mean fecal excretion was 13% of the administered dose. Parent drug was the major radioactive component in plasma, urine, and feces, with only 16% of the dose excreted as metabolites (13% in urine and 3% in feces), indicating that sitagliptin was eliminated primarily by renal excretion. Approximately 74% of plasma AUC of total radioactivity was accounted for by parent drug. Six metabolites were detected at trace levels, each representing <1 to 7% of the radioactivity in plasma. These metabolites were the N-sulfate and N-carbamoyl glucuronic acid conjugates of parent drug, a mixture of hydroxylated derivatives, an ether glucuronide of a hydroxylated metabolite, and two metabolites formed by oxidative desaturation of the piperazine ring followed by cyclization. These metabolites were detected also in urine, at low levels. Metabolite profiles in feces were similar to those in urine and plasma, except that the glucuronides were not detected in feces. CYP3A4 was the major cytochrome P450 isozyme responsible for the limited oxidative metabolism of sitagliptin, with some minor contribution from CYP2C8.

Potential for Interactions between Caspofungin and Nelfinavir or Rifampin

ABSTRACT The potential for interactions between caspofungin and nelfinavir or rifampin was evaluated in two parallel-panel studies. In study A, healthy subjects received a 14-day course of caspofungin alone (50 mg administered intravenously [IV] once daily) (n = 10) or with nelfinavir (1,250 mg administered orally twice daily) (n = 9) or rifampin (600 mg administered orally once daily) (n = 10). In study B, 14 subjects received a 28-day course of rifampin (600 mg administered orally once daily), with caspofungin (50 mg administered IV once daily) coadministered on the last 14 days, and 12 subjects received a 14-day course of caspofungin alone (50 mg administered IV once daily). The coadministration/administration alone geometric mean ratio for the caspofungin area under the time-concentration profile calculated for the 24-h period following dosing [AUC0-24] was as follows (values in parentheses are 90% confidence intervals [CIs]): 1.08 (0.93-1.26) for nelfinavir, 1.12 (0.97-1.30) for rifampin (study A), and 1.01 (0.91-1.11) for rifampin (study B). The shape of the caspofungin plasma profile was altered by rifampin, resulting in a 14 to 31% reduction in the trough concentration at 24 h after dosing (C24h), consistent with a net induction effect at steady state. Both the AUC and the C24h were elevated in the initial days of rifampin coadministration in study A (61 and 170% elevations, respectively, on day 1) but not in study B, consistent with transient net inhibition prior to full induction. The coadministration/administration alone geometric mean ratio for the rifampin AUC0-24 on day 14 was 1.07 (90% CI, 0.83-1.38). Nelfinavir does not meaningfully alter caspofungin pharmacokinetics. Rifampin both inhibits and induces caspofungin disposition, resulting in a reduced C24h at steady state. An increase in the caspofungin dose to 70 mg, administered daily, should be considered when the drug is coadministered with rifampin.

Interactions between Simvastatin and Troglitazone or Pioglitazone in Healthy Subjects

Two randomized, two‐period crossover studies were conducted to evaluate the effects of repeat oral dosing of troglitazone (Study I) and pioglitazone (Study II) on the pharmacokinetics of plasma HMG‐CoA reductase inhibitors following multiple oral doses of simvastatin and of simvastatin on the plasma pharmacokinetics of troglitazone (Study I) in healthy subjects. In both studies, each subject received two treatments. Treatment A consisted of once‐daily oral doses of troglitazone 400 mg (Study I) or pioglitazone 45 mg (Study II) for 24 days with coadministration of once‐daily doses of simvastatin 40 mg (Study I) or 80 mg (Study II) on Days 15 through 24. Treatment B consisted of once‐daily oral doses of simvastatin 40 mg (Study I) or 80 mg (Study II) for 10 days. In Study I, the area under the plasma concentration‐time profiles (AUC) and maximum plasma concentrations (Cmax) of HMG‐CoA reductase inhibitors in subjects who received both troglitazone and simvastatin were decreased modestly (by ∼30% for Cmax and ∼40% for AUC), but time to reach Cmax(tmax) did not change, as compared with those who received simvastatin alone. Simvastatin, administered orally as a 40 mg tablet daily for 10 days, did not affect the AUC or tmax (p > 0.5) but caused a small but clinically insignificant increase (∼25%) in Cmax for troglitazone. In Study II, pioglitazone, at the highest approved dose for clinical use, did not significantly alter any of the pharmacokinetic parameters (AUC, Cmax, and tmax) of simvastatin HMG‐CoA reductase inhibitory activity. For all treatment regimens, side effects were mild and transient, suggesting that coadministration of simvastatin with either troglitazone or pioglitazone was well tolerated. The modest effect of troglitazone on simvastatin pharmacokinetics is in agreement with the suggestion that troglitazone is an inducer of CYP3A. The insignificant effect of simvastatin on troglitazone pharmacokinetics is consistent with the conclusion that simvastatin is not a significant inhibitor for drug‐metabolizing enzymes. The lack of pharmacokinetic effect of pioglitazone on simvastatin supports the expectation that this combination may be used safely.

Single- and multiple-dose administration of caspofungin in patients with hepatic insufficiency: implications for safety and dosing recommendations.

This report investigated safety and dosing recommendations of intravenous caspofungin in hepatic insufficiency. In the single‐dose study, 8 patients each with mild and moderate hepatic insufficiency received 70 mg of caspofungin. In the multiple‐dose study, 8 patients with mild hepatic insufficiency and 13 healthy matched controls received 70 mg on day 1 and 50 mg daily on days 2 through 14. Eight patients with moderate hepatic insufficiency received 70 mg on day 1 and 35 mg daily on days 2 through 14. Caspofungin was generally well tolerated with no discontinuations due to serious or nonserious adverse experiences. The area under the concentration‐time profile over the interval of last quantifiable point to infinity (AUC0‐∞) geometric mean ratio (GMR) (90% confidence interval [CI]) for mild hepatic insufficiency/historical controls was 1.55 (1.32–1.86) in the single‐dose study and for mild hepatic insufficiency/concurrent controls was 1.21 (1.04–1.39) for day 14 area under the concentration– time profile calculated over the interval 0 to 24 hours (AUC0‐24h) following multidose. The AUC0‐∞ GMR (90% CI) for moderate hepatic insufficiency/historical controls was 1.76 (1.51–2.06) following 70 mg; AUC0‐24h GMR (90% CI) for moderate hepatic insufficiency/concurrent controls was 1.07 (0.90–1.28) on day 14 after 35 mg daily. No dosage adjustment is recommended for patients with mild hepatic insufficiency. A dosage reduction to 35 mg daily following the 70‐mg loading dose is recommended for patients with moderate hepatic insufficiency.

Pharmacokinetics of Long‐Acting Naltrexone in Subjects With Mild to Moderate Hepatic Impairment

Long‐acting naltrexone is an extended‐release formulation developed with the goal of continuous naltrexone exposure for 1 month for the treatment of alcohol dependence. The influence of mild and moderate hepatic impairment on naltrexone pharmacokinetics following long‐acting naltrexone 190‐mg administration was assessed. Subjects with mild (Child‐Pugh grade A) and moderate (Child‐Pugh grade B) hepatic impairment (n = 6 per group) and matched control subjects (n = 13) were enrolled. Naltrexone and 6β‐naltrexol concentrations were determined over a period of 63 days following a single intramuscular dose. Naltrexone and 6β‐naltrexol concentrations were detected in all subjects through 28 days. Total exposure (AUC0‐∞) of naltrexone and 6β‐naltrexol was similar across all groups. The long apparent half‐lives of naltrexone and 6β‐naltrexol (5–8 days) were attributed to the slow release of naltrexone (long‐acting naltrexone exhibits absorption rate‐limited elimination or “flip‐flop” kinetics); elimination was not altered in subjects with hepatic impairment. Based on pharmacokinetic considerations, the dose of long‐acting naltrexone does not need to be adjusted in patients with mild or moderate hepatic impairment.

Safety and pharmacokinetics of multiple doses of aclidinium bromide administered twice daily in healthy volunteers

Chronic obstructive pulmonary disease (COPD) is characterized by progressive airway obstruction and increased cholinergic tone. The global initiative for chronic obstructive lung disease (GOLD) guidelines recommend long-acting anticholinergics for COPD maintenance treatment. Aclidinium bromide is a novel, long-acting muscarinic antagonist developed for the treatment of COPD. A phase I, randomized, single-blind, multiple-dose clinical trial was conducted to assess the safety and pharmacokinetics (PK) of multiple doses of twice-daily (BID) aclidinium in healthy subjects. Thirty healthy male and female subjects received aclidinium 200 μg, 400 μg, 800 μg, or placebo twice daily for 7 days. Subjects were randomized to 1 of 3 cohorts and 10 subjects in each cohort were randomized (8:2) to either aclidinium or placebo groups. Safety was assessed via adverse events (AEs), laboratory evaluations, vital signs, and ECGs. Plasma samples were obtained at multiple time points throughout the study and analyzed for aclidinium and its inactive acid and alcohol metabolites using a fully validated method of liquid chromatography coupled with tandem mass spectrometry. A total of 9 treatment-emergent AEs were reported (1, placebo; 3, aclidinium 400 μg; 5, aclidinium 800 μg), all of which were mild in severity. No serious AEs were reported. There were no clinically meaningful changes in laboratory parameters or vital signs. PK parameters on Day 7 following BID dosing of aclidinium showed that steady state was achieved for aclidinium and its metabolites. On Days 1 and 7, maximum plasma concentrations (Cmax) of aclidinium were generally observed at the first PK time point (5 min postdose) and rapidly declined, with plasma concentrations generally less than 10% of Cmax by 6 h postdose in all aclidinium groups. Mean effective t(½) after the evening dose on Day 7 ranged from 4.6 to 7.0 h for aclidinium 400 μg and 800 μg, similar to the terminal t(½) observed on Day 1 (4.5-5.9 h). Exposure for aclidinium and both metabolites increased with increasing dose, with the increase in exposure being less than dose proportional between the 400 μg and 800 μg doses. Overall, all doses of aclidinium were safe and well tolerated throughout the study. Pharmacokinetic steady state was reached for aclidinium and both metabolites within the 7-day treatment period for all doses tested. Aclidinium bromide exhibited time-independent PK following dosing to steady state, indicating that similar concentration versus time profiles will occur after repeated administration at the same dose and frequency.

Pharmacokinetics and safety of ebastine in patients with impaired hepatic function compared with healthy volunteers: a phase I open-label study.

AbstractObjective: To assess the differences between patients with hepatic insufficiency and healthy subjects with regard to the pharmacokinetics, cardiac safety and overall safety of ebastine and its active metabolite carebastine. Design: Open-label parallel-group study. Participants: 24 patients with varying degrees of hepatic insufficiency, as categorised by the Child-Pugh classification, and 12 healthy volunteers. Methods: Healthy subjects and patients with Child-Pugh class A (n = 8) or B (n = 8) received ebastine 20mg once daily for 7 days. Patients with Child-Pugh class C (n = 8) [single or repeated dose] received ebastine 10mg. Plasma concentrations of ebastine and carebastine were determined for 23.5 hours following the initial dose on day 1 and for 96 hours following the dose on day 7 by using a sensitive liquid chromatography-tandem mass spectrometry assay with a minimum quantifiable limit of 0.05 µg/L for ebastine and 1.00 µg/L for carebastine. Hepatic function was assessed by blood clearance of indocyanine green 0.5 mg/kg administered intravenously on day 2. Cardiac and overall safety parameters were monitored. Results: Overall, the pharmacokinetics of ebastine were not modified by hepatic impairment. No correlation between ebastine pharmacokinetics and hepatic function, as expressed by indocyanine green clearance, was observed. Comparison of the effective half-life of ebastine and carebastine between groups did not show relevant differences. Therefore, no apparent accumulation of ebastine occurred, and steady-state concentrations of ebastine and carebastine were predictable from single-dose pharmacokinetics both in healthy subjects and in hepatically impaired patients. Finally, no apparent difference was noted in the safety of ebastine between patients with hepatic insufficiency and healthy subjects as assessed by evaluation of adverse events, vital signs and laboratory parameters. Conclusion: Ebastine can be safely administered to patients with impaired hepatic function, as no clinically important differences can be anticipated from the pharmacokinetics and safety profile of ebastine/carebastine as compared with healthy subjects. Nevertheless, the dosage used in severely impaired patients (10mg daily) was half that used in patients with mild to moderate impairment, and any comedication did not include drugs affecting liver function; in clinical practice, both these factors should be taken into account.

Pharmacokinetics and pharmacodynamics of single and multiple doses of the glucagon receptor antagonist LGD‐6972 in healthy subjects and subjects with type 2 diabetes mellitus

To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple doses of a novel, oral glucagon receptor antagonist, LGD‐6972, in healthy subjects and subjects with type 2 diabetes (T2DM).

Pharmacokinetics and Pharmacodynamics of Zolmitriptan in Patients with Mild to Moderate Hypertension: A Double‐Blind, Placebo‐Controlled Study

Zolmitriptan is a potent selective 5HT1B/1D receptor agonist for acute migraine therapy. Zolmitriptan has vasoconstrictor activity in cerebral vessels and may cause slight elevations of blood pressure in subjects without hypertension. Therefore, the pharmacokinetics and pharmacodynamics of zolmitriptan (5, 10, and 20 mg) were evaluated in 16 patients with mild to moderate hypertension (controlled by hydrochlorothiazide 50 mg once daily) and 17 healthy age‐ and sex‐matched control subjects in a randomized, placebo‐controlled, double‐blind, four‐period crossover study. The pharmacokinetics of zolmitriptan and its metabolites were dose proportional. Although area under the concentration‐time curve (AUC0‐∞) and maximum concentration (Cmax) were slightly higher in patients with hypertension at all doses, this was only statistically significant for AUC at the 20‐mg dose. Differences between subjects with and without hypertension were not clinically significant. Zolmitriptan produced a small increase in blood pressure, but this was similar in subjects with and without hypertension and was of no clinical significance. Zolmitriptan was well tolerated in both groups. Zolmitriptan plasma concentrations were higher in women than in men, with higher values of AUC and Cmax and lower total clearance in women. These results indicate that zolmitriptan can be administered for treatment of migraine in patients with controlled hypertension without dose adjustment.