Patrick Larson

Induction of Adipocyte Complement-Related Protein of 30 Kilodaltons by PPARγ Agonists: A Potential Mechanism of Insulin Sensitization

Adipocyte complement-related protein of 30 kDa (Acrp30, adiponectin, or AdipoQ) is a fat-derived secreted protein that circulates in plasma. Adipose tissue expression of Acrp30 is lower in insulin-resistant states and it is implicated in the regulation of in vivo insulin sensitivity. Here we have characterized the ability of PPARγ agonists to modulate Acrp30 expression. After chronic treatment of obese-diabetic (db/db) mice with PPARγ agonists (11 d), mean plasma Acrp30 protein levels increased (>3×). Similar effects were noted in a nongenetic type 2 diabetes model (fat-fed and low-dose streptozotocin-treated mice). In contrast, treatment of mice (db/db or fat-fed) with metformin or a PPARα agonist did not affect plasma Acrp30 protein levels. In a cohort of normal human subjects, 14-d treatment with rosiglitazone also produced a 130% increase in circulating Acrp30 levels vs. placebo. In addition, circulating Acrp30 levels were suppressed 5-fold in patients with severe insulin resistance in association wit...

Pharmacokinetics and bioavailability of montelukast sodium (MK-0476) in healthy young and elderly volunteers

A study was conducted to (i) characterize the multiple‐dose pharmacokinetics of oral montelukast sodium (MK‐0476), 10 mg d−1 in healthy young subjects (N =12), (ii) evaluate the pharmacokinetics of montelukast in healthy elderly subjects (N =12), and (iii) compare the pharmacokinetics and oral bioavailability of montelukast between elderly and young subjects. Following oral administration of montelukast sodium, 10 mg d−1 (the therapeutic regimen for montelukast sodium) for 7 d, there was little difference in the plasma concentration–time profiles of montelukast in young subjects between day 1 and day 7 dosing. On average, trough plasma concentrations of montelukast were nearly constant, ranging from 18 to 24 ng mL−1 on days 3–7, indicating that the steady state of montelukast was attained on day 2. The mean accumulation ratio was 1·14, indicating that this dose regimen results in a 14% accumulation of montelukast. In elderly subjects, mean values of plasma clearance (Cl), steady‐state volume of distribution (Vss), plasma terminal half‐life (t1/2), and mean residence time in the body (MRTIV) following a 7 mg intravenous (5 min infusion) administration of montelukast sodium in the elderly were 30·8 mL min−1, 9·7 L, 6·7 h, and 5·4 h, respectively. Following a 10 mg oral dose, the bioavailability of montelukast in healthy elderly averaged 61%, very close to that (62%) determined previously in healthy young subjects. Also following the 10 mg oral administration, the mean values of AUC0→∞, Cmax, tmax, and t1/2, and the mean plasma concentration–time profile of montelukast in the elderly, were generally similar to those in young subjects, indicating that age has little or no effect on the pharmacokinetics of montelukast. There is no need to modify dosage as a function of age.

Effect of a Single Cyclosporine Dose on the Single‐Dose Pharmacokinetics of Sitagliptin (MK‐0431), a Dipeptidyl Peptidase‐4 Inhibitor, in Healthy Male Subjects

Sitagliptin (MK‐0431) is an orally active, potent, and selective dipeptidyl peptidase‐4 inhibitor used for the treatment of patients with type 2 diabetes mellitus. Sitagliptin has been shown to be a substrate for P‐glycoprotein in preclinical studies. Cyclosporine was used as a probe P‐glycoprotein inhibitor at a high dose to evaluate the potential effect of potent P‐glycoprotein inhibition on single‐dose sitagliptin pharmacokinetics in healthy male subjects. Eight healthy young men received a single oral 600‐mg dose of cyclosporine with a single 100‐mg oral sitagliptin dose and a single oral 100‐mg sitagliptin dose alone in an open‐label, randomized, 2‐period, crossover study. Single doses of sitagliptin with or without single doses of cyclosporine were generally well tolerated. The sitagliptin AUC0‐∞ geometric mean ratio was 1.29 with a 90% confidence interval of (1.24, 1.34). The sitagliptin Cmax geometric mean ratio was 1.68 with a 90% confidence interval of (1.35, 2.08). Cyclosporine coadministration did not appear to affect apparent sitagliptin renal clearance, t1/2, or C24 h, suggesting that effects of these high doses of cyclosporine are more likely due to enhanced absorption of sitagliptin, potentially through inhibition of intestinal P‐glycoprotein. These results rationalize the use of a single high‐dose cyclosporine as a probe inhibitor of P‐glycoprotein for compound candidates whose elimination is less dependent on CYP3A4‐mediated metabolism.

Montelukast Dose Selection in Children Ages 2 to 5 Years: Comparison of Population Pharmacokinetics between Children and Adults

Montelukast, a leukotriene receptor antagonist, has demonstrated efficacy and tolerability in the treatment of asthma in patients age 6 years and older. The purpose of this open, one‐period, multicenter population pharmacokinetic study was to identify a chewable tablet (CT) dose of montelukast for administration to children ages 2 to 5 years with asthma, yielding a single‐dose pharmacokinetic profile (area under the plasma concentration‐time curve [AUC]) comparable to that of the 10 mg film‐coated tablet (FCT) dose in adults. Because patient numbers were small and the volume of blood that could be collected from individual 2‐ to 5‐year‐old patients was limited, a population pharmacokinetic approach was used to estimate population AUC (AUCpop). The 4 mg CT dose of montelukast was well tolerated and yielded an AUCpop (2721 ng·h/mL) similar to that of the adult AUCpop (2595 ng·h/mL) observed after a 10 mg FCT dose. These results support the selection of a 4 mg once‐daily CT dose of montelukast for future efficacy and safety studies in children ages 2 to 5 years with asthma.

Comparative inhibitory activity of etoricoxib, celecoxib, and diclofenac on COX-2 versus COX-1 in healthy subjects.

We determined cyclo‐oxygenase‐1 and cyclo‐oxygenase‐2 inhibition in healthy middle‐aged subjects (41–65 years) randomly assigned to four 7‐day treatment sequences of etoricoxib 90 mg every day, celecoxib 200 mg twice a day, diclofenac 75 mg twice a day, or placebo in a double‐blind, randomized, 4‐period crossover study. Maximum inhibition of thromboxane B2 (cyclo‐oxygenase‐1 activity) in clotting whole blood on day 7 (0–24 hours postdose) was the primary endpoint. Inhibition of lipopolysaccharide‐induced prostaglandin E2 in whole blood (cyclo‐oxygenase‐2 activity) was assessed on day 7 (0–24 hours postdose) as a secondary endpoint. Diclofenac had significantly greater maximum inhibition of thromboxane B2 versus each comparator (P < .001); placebo 2.4% (95% confidence interval: −8.7% to 12.3%), diclofenac 92.2% (91.4% to 92.9%), etoricoxib 15.5% (6.6% to 23.5%), and celecoxib 20.2% (11.5% to 28.1%). Prostaglandin E2 synthesis was inhibited with a rank order of potency of diclofenac > etoricoxib > celecoxib. In summary, at doses commonly used in rheumatoid arthritis, diclofenac significantly inhibits both cyclo‐oxygenase‐1 and cyclo‐oxygenase‐2, whereas etoricoxib and celecoxib significantly inhibit cyclo‐oxygenase‐2 and do not substantially inhibit cyclo‐oxygenase‐1.

Effect of Different Durations of Ketoconazole Dosing on the Single-Dose Pharmacokinetics of Midazolam: Shortening the Paradigm

Given the prominent role of cytochrome P450 3A (CYP3A) in the metabolism of drugs, it is critical to determine whether new chemical entities will be affected by the inhibition of this enzyme system and result in clinically relevant drug interactions. Ketoconazole interaction studies are frequently performed to determine a given compounds sensitivity to CYP3A metabolism. The present study evaluated whether probing a sensitive substrate (midazolam) with a potent inhibitor (ketoconazole) at earlier time points (days 1 or 2) might be used to reliably gauge the magnitude of a meaningful interaction. The geometric mean ratios (ketoconazole + midazolamday 5/ketoconazole + midazolamday 1 and ketoconazole + midazolamday 5/ketoconazole + midazolamday 2) for midazolam AUC0‐∞ were 1.36 and 1.06 with corresponding 90% confidence intervals of (1.17, 1.57) and (0.83, 1.23), respectively. These findings suggest that short‐term drug‐drug interaction studies can predict the magnitude of change in AUC as reliably as studies using longer duration treatments.

Evaluation of pharmacokinetic parameters and dipeptidyl peptidase-4 inhibition following single doses of sitagliptin in healthy, young Japanese males.

AIMS Sitagliptin is a selective inhibitor of dipeptidyl peptidase-4 (DPP-4) used to treat type 2 diabetes. The present aim was to evaluate pharmacokinetic (PK), pharmacodynamic (PD) and safety characteristics of sitagliptin following single doses in healthy, young Japanese males. METHODS In this alternating two-panel, randomized, controlled double-blind study, six healthy Japanese male subjects (aged 20-46 years) in each panel received single oral doses of 5-400mg sitagliptin and two received placebo. Plasma and urine drug concentrations were measured from 0-48h post dose and plasma DPP-4 inhibition from 0-24h post dose. The results were compared with historical data from young, healthy non-Japanese males. RESULTS Plasma concentrations of sitagliptin increased approximately in proportion to dose; maximum concentrations occurred 2-6h post-dose. The mean apparent terminal half-life for plasma sitagliptin was 9-14h, with the half-life slightly decreasing as the dose increased. The mean dose fraction excreted unchanged in the urine was 0.73-1.00. Ingestion of a traditional Japanese breakfast prior to dosing had only a minor effect on PK parameters. After correction for dilution and competition effects during assay, doses of sitagliptin ≥50mg resulted in weighted average DPP-4 inhibition from 0-24h post-dose >94% (without correction, >78%). No clinically meaningful differences in PK and DPP-4 inhibition parameters were found between Japanese and non-Japanese subjects. Sitagliptin was generally well tolerated and there were no serious adverse experiences or episodes of hypoglycaemia. CONCLUSIONS The PK and PD findings from this study are consistent with once daily dosing of sitagliptin in Japanese patients with type 2 diabetes.

Individual and Combined Effects of Peroxisome Proliferator-Activated Receptor α and γ Agonists, Fenofibrate and Rosiglitazone, on Biomarkers of Lipid and Glucose Metabolism in Healthy Nondiabetic Volunteers

This open‐label, randomized, placebo‐controlled, incomplete‐block, 3‐period crossover pilot study investigated the effects of peroxisome proliferator‐activated receptor α‐ and γ‐agonists on biomarkers of lipid and glucose metabolism in 12 nondiabetic subjects. Plasma samples were collected before and after each 14‐day treatment with placebo, fenofibrate (201 mg/d), rosiglitazone (4 mg twice daily), and combined fenofibrate (201 mg/d) plus rosiglitazone (4 mg twice daily). Except for triglycerides (P < .042) and free fatty acids (P <.074), no significant interaction was demonstrated between fenofibrate and rosiglitazone; thus, the effect due to each drug alone was evaluated (presence/absence of drug). Fenofibrate significantly (P < .050) increased lipoprotein lipase activity (35%) and decreased apolipoproteins B (13%) and C‐III (20%). Rosiglitazone significantly (P < .050) decreased fasting glucose (7.3%) and increased apolipoprotein C‐III (19%) and adiponectin (137%). Fenofibrate and rosiglitazone also produced effects on triglyoerides and free fatty acids, but it was not possible to determine if these effects were synergistic in nature.

Effect of Different Durations and Formulations of Diltiazem on the Single‐Dose Pharmacokinetics of Midazolam: How Long Do We Go?

Understanding how inhibition of cytochrome P4503A (CYP3A) affects the metabolism of a new drug is critical in determining if a clinically relevant drug interaction will occur. Diltiazem interaction studies assess a given compounds sensitivity to moderate CYP3A inhibition. The present study compared the effect different durations and formulations of diltiazem (extended release [XR] and conventional release [CR]) had on the single‐dose pharmacokinetics of midazolam. The geometric mean ratio (GMR; midazolam + diltiazemXR × 5 days/midazolam + diltiazemXR × 2 days) for midazolam AUC0‐∞ was 0.98 (90% confidence interval [CI], 0.87, 1.10). The GMR (midazolam + diltiazemXR × 2 days/midazolam + diltiazemCR × 2 days) for midazolam AUC0‐∞ was 0.82 (90% CI, 0.73, 0.92). Simcyp simulations accurately predicted the observed clinical results only when a hepatic CYP3A degradation rate (kdeg) different from that provided by the software was used. The data suggest that dosing diltiazem XR for 2 days predicts the change in midazolam AUC as reliably as 5 days of XR dosing and 2 days of CR dosing. In addition, the authors believe that a hepatic CYP3A kdeg of 0.03 h−1 should be considered for future Simcyp studies.

Laropiprant in Combination With Extended‐Release Niacin Does Not Alter Urine 11‐Dehydrothromboxane B2, a Marker of In Vivo Platelet Function, in Healthy, Hypercholesterolemic, and Diabetic Subjects

Laropiprant, an antagonist of the PGD2 receptor, DP1, is effective in reducing the flushing symptoms associated with extended‐release (ER) niacin and thereby improves the tolerability of niacin therapy for dyslipidemia. Because PGD2 has been reported to inhibit platelet aggregation in vitro, it has been speculated that antagonism of DP1 may enhance platelet reactivity. Three clinical studies evaluated the potential effect of laropiprant, with or without coadministration of ER niacin, on in vivo platelet function in healthy subjects and hypercholesterolemic or diabetic subjects by measuring urinary levels of 11‐dehydrothromboxane B2 (11‐dTxB2), a marker of in vivo platelet activation. Following 7 days of multiple‐dose administration, coadministration of laropiprant with ER niacin did not increase urinary 11‐dTxB2 levels compared to ER niacin alone in healthy, hypercholesterolemic, or diabetic subjects. In hypercholesterolemic and diabetic subjects, laropiprant did not increase urinary 11‐dTxB2 levels compared to placebo. These results demonstrate that laropiprant does not enhance in vivo platelet reactivity, either alone or in combination with niacin.