Wesley Tanaka

Pharmacokinetics and pharmacodynamics of sitagliptin, an inhibitor of dipeptidyl peptidase IV, in healthy subjects: results from two randomized, double-blind, placebo-controlled studies with single oral doses.

Sitagliptin (MK‐0431 [(2R)‐4‐oxo‐4‐(3‐[trifluoromethyl]‐5,6‐dihydro[1,2,4]triazolo[4,3‐a]pyrazin‐7[8H]‐yl)‐1‐(2,4,5‐trifluorophenyl)butan‐2‐amine]) is an orally active, potent, and selective inhibitor of dipeptidyl peptidase IV (DPP‐IV) currently in phase III development for the treatment of type 2 diabetes.

Comparative Inhibitory Activity of Rofecoxib, Meloxicam, Diclofenac, Ibuprofen, and Naproxen on COX‐2 versus COX‐1 in Healthy Volunteers

Steady‐state inhibitory activity of rofecoxib (Vioxx™) on COX‐2 versus COX‐1 was compared with that of commonly used nonsteroidal anti‐inflammatory drugs (NSAIDs) in 76 healthy volunteers randomized to placebo, rofecoxib 12.5 mg qd, rofecoxib 25 mg qd, diclofenac 50 mg tid, ibuprofen 800 mg tid, sodium naproxen 550 mg bid, or meloxicam 15 mg qd. All of these doses include the high end of the approved clinical dose range. Ex vivo whole‐blood assays were used to determine the effect on COX‐2 and COX‐1 activity, respectively. Urinary prostanoids were also measured. Mean inhibition of COX‐2 (measured as the weighted average inhibition [WAI] of lipopolysaccharide [LPS]‐induced PGE2 generation over 8 hours on day 6 vs. baseline) was −2.4%, 66.7%, 69.2%, 77.5%, 93.9%, 71.4%, and 71.5% for placebo, rofecoxib 12.5 mg, rofecoxib 25 mg, meloxicam, diclofenac, ibuprofen, and naproxen, respectively. Corresponding values for mean inhibition of COX‐1 (measured as TXB2 generation in clotting whole blood) were −5.15%, 7.98%, 6.65%, 53.3%, 49.5%, 88.7%, and 94.9%. Rofecoxib had no significant effect on urinary excretion of 11‐dehydro TXB2, a COX‐ 1‐derived product. These data support the contention that rofecoxib is the only drug of the regimens tested that uniquely inhibits COX‐2 without affecting COX‐1.

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.

The effects of finasteride on scalp skin and serum androgen levels in men with androgenetic alopecia

BACKGROUND Data suggest that androgenetic alopecia is a process dependent on dihydrotestosterone (DHT) and type 2 5alpha-reductase. Finasteride is a type 2 5alpha-reductase inhibitor that has been shown to slow further hair loss and improve hair growth in men with androgenetic alopecia. OBJECTIVE We attempted to determine the effect of finasteride on scalp skin and serum androgens. METHODS Men with androgenetic alopecia (N = 249) underwent scalp biopsies before and after receiving 0.01, 0.05, 0.2, 1, or 5 mg daily of finasteride or placebo for 42 days. RESULTS Scalp skin DHT levels declined significantly by 13.0% with placebo and by 14.9%, 61.6%, 56. 5%, 64.1%, and 69.4% with 0.01, 0.05, 0.2, 1, and 5 mg doses of finasteride, respectively. Serum DHT levels declined significantly (P <.001) by 49.5%, 68.6%, 71.4%, and 72.2% in the 0.05, 0.2, 1, and 5 mg finasteride treatment groups, respectively. CONCLUSION In this study, doses of finasteride as low as 0.2 mg per day maximally decreased both scalp skin and serum DHT levels. These data support the rationale used to conduct clinical trials in men with male pattern hair loss at doses of finasteride between 0.2 and 5 mg.

A Phase I Trial of the Dual Farnesyltransferase and Geranylgeranyltransferase Inhibitor L-778,123 and Radiotherapy for Locally Advanced Pancreatic Cancer

Purpose: Preclinical and clinical studies have demonstrated that inhibition of prenylation can radiosensitize cell lines with activation of Ras and produce clinical response in patients with cancer. The aim of this study was to determine the maximally tolerated dose of the dual farnesyltransferase and geranylgeranyltransferase I inhibitor L-778,123 in combination with radiotherapy for patients with locally advanced pancreatic cancer. Experimental Design: L-778,123 was given by continuous intravenous infusion with concomitant radiotherapy to 59.4 Gy in standard fractions. Two L-778,123 dose levels were tested: 280 mg/m2/day over weeks 1, 2, 4, and 5 for dose level 1; and 560 mg/m2/day over weeks 1, 2, 4, 5, and 7 for dose level 2. Results: There were no dose-limiting toxicities observed in the eight patients treated on dose level 1. Two of the four patients on dose level 2 experienced dose-limiting toxicities consisting of grade 3 diarrhea in one case and grade 3 gastrointestinal hemorrhage associated with grade 3 thrombocytopenia and neutropenia in the other case. Other common toxicities were mild neutropenia, dehydration, hyperglycemia, and nausea/vomiting. One patient on dose level 1 showed a partial response of 6 months in duration. Both reversible inhibition of HDJ2 farnesylation and radiosensitization of a study patient-derived cell line were demonstrated in the presence of L-778,123. K-RAS mutations were found in three of the four patients evaluated. Conclusions: The combination of L-778,123 and radiotherapy at dose level 1 showed acceptable toxicity in patients with locally advanced pancreatic cancer. Radiosensitization of a patient-derived pancreatic cancer cell line was observed.

Biochemical activity, pharmacokinetics, and tolerability of MK‐886, a leukotriene biosynthesis inhibitor, in humans

MK‐886, a leukotriene biosynthesis inhibitor, was evaluated in double‐blind, placebo‐controlled, randomized single‐ and multiple‐dose studies in 12 and 24 healthy male subjects, respectively. The effects of a single dose (250, 500, and 750 mg) and multiple doses (100 mg and 250 mg every 8 hours) of MK‐886 on calcium ionophore stimulated leukotriene B4 synthesis ex vivo in whole blood were evaluated. Inhibition of leukotriene B4 biosynthesis ex vivo occurred in a dose‐related manner up to a 500 mg single dose, and 250 mg every 8 hours. A single dose of 500 mg MK‐886 significantly inhibited leukotriene B4 biosynthesis by a maximum of 60% at 2 hours after the dose (p < 0.05). Multiple doses of 250 mg significantly inhibited leukotriene B4 biosynthesis by a maximum of 52% at 2 hours after the dose (p < 0.05). The degree of leukotriene B4 inhibition ex vivo in whole blood significantly correlated with plasma MK‐886 concentrations (r = 0.78). In conclusion, the single and multiple doses of MK‐886 evaluated in this study were well tolerated overall and partially inhibited leukotriene B4 biosynthesis ex vivo in whole blood.

Quantitative measurement of cysteinyl leukotrienes and leukotriene B4 in human sputum using ultra high pressure liquid chromatography–tandem mass spectrometry

The role of leukotrienes (LTs) in airway inflammatory diseases, such as asthma, has been extensively reported. The measurement of LTs in sputum supernatants, which is commonly done via enzyme immunoassays (EIAs), may prove to be useful for assessing airway inflammation. Despite the many advantages of EIA, these methods suffer from a lack of selectivity. Therefore, a selective and reliable method for the analysis of LTs in human sputum is needed. In this study we developed and validated a sensitive and specific method using ultra high pressure liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS), to measure simultaneously cysteinyl leukotrienes (CysLTs) and leukotriene B₄ (LTB₄) in human sputum. Sputum supernatants obtained by ultracentrifugation were stabilized by protease inhibitors, spiked with stable isotopic internal standards, and subjected to solid phase extraction (SPE) and UHPLC separation. Multiple reaction monitoring (MRM) transitions were optimized and measured on a mass spectrometer. The limit of detection (LOD) for LTE₄ and LTB₄ was 9.8 and 19.5 pg/mL, respectively. The lower limit of quantitation (LLOQ) for LTE₄ and LTB₄ was 19.5 and 39.0 pg/mL, respectively. The dynamic range of the LTE₄ assay was from 9.8 to 5000 pg/mL, whereas for the LTB₄ assay was from 19.5 to 10,000 pg/mL. The intra- and inter-day % coefficient of variation (%CV) was <6.5% and <10%, for both LTE₄ and LTB₄, respectively. Spike recovery ranged from 105% to 111% for both analytes. In addition, twenty-two sputum samples were analyzed for cysLTs and LTB₄. Fourteen of these samples were purchased commercially and eight were collected during the course of a clinical trial. LTB₄ was detectable in all samples tested and it ranged from 79 to 7220 pg/mL. LTE₄ was detectable in most of the sputum samples (12.3-891 pg/mL), whereas LTC₄ and LTD₄ were below limit of detection for majority of sputum samples. The in vitro conversion of LTC₄ and LTD₄ into LTE₄ was observed. The measurement of LTB₄ was sensitive to low pH and high temperature. The use of UHPLC-MS/MS method will allow a more accurate and reliable quantitation of LTs in human sputum, which in turn, may lead to a better understanding of the role of LTs in airway disease pathways and the application in associated clinical treatments.

A Dual PPAR α/γ Agonist Increases Adiponectin and Improves Plasma Lipid Profiles in Healthy Subjects

AbstractBackground: The objective of these studies was to evaluate the pharmacokinetics and pharmacodynamics of MK-0767, a prototypical dual peroxisome proliferator-activated receptor (PPAR) α/γ agonist, following administration of single and multiple oral doses in healthy male subjects. Methods: The first study was a double-blind, randomised, placebo-controlled, alternating two-panel, rising dose protocol in which single doses of l–80mg of MK-0767 were administered. The second study was a double-blind, randomised, placebo-controlled, staggered incremental dose, parallel-group protocol in which multiple doses of 0.3–25mg of MK-0767 were administered once daily for 14 days. In both studies at each dose level, six subjects received MK-0767 and two subjects received placebo. Results: Plasma area under the concentration-time curve and maximum plasma concentration increased with single and multiple doses of MK-0767 over the dose ranges studied. The apparent terminal half-life of MK-0767 averaged ≈36 hours following single and multiple doses. Steady-state plasma concentrations were achieved following ≈8 days of multiple doses. Compared with placebo, MK-0767 produced dose-dependent reductions in triglycerides (−26 ± 8% [p = 0.002] and −33 ± 13% [p = 0.008]) and free fatty acids (−50 ± 11% [p < 0.001] and −67 ± 23% [p = 0.008]) following single and multiple doses, respectively. Significant (p < 0.050) dose-dependent alterations in adiponectin (332 ± 36%), low-density lipoprotein cholesterol (−29 ± 5%), total cholesterol (−19 ± 3%), non-high-density lipoprotein cholesterol (−28 ± 4%), and fasting plasma glucose (−6 ± 2%; only in the 25mg group) were observed after multiple doses. Conclusions: The observed effects of MK-0767 on adiponectin, free fatty acids and lipids, even after single doses, demonstrate that this prototypical dual PPAR α/γ agonist has clinically meaningful activity in vivo.

Inhibition of prostacyclin and thromboxane biosynthesis in healthy volunteers by single and multiple doses of acetaminophen and indomethacin

This double‐blind, randomized crossover study assessed the effect of acetaminophen (1000 mg every 8 hours) versus indomethacin (50 mg every 8 hours) versus placebo on cyclooxygenase enzymes (COX‐1 and COX‐2). Urinary excretion of 2,3‐dinor‐6‐keto‐PGF1α, (prostacyclin metabolite, PGI‐M; COX‐2 inhibition) and 11‐dehydro thromboxane B2 (thromboxane metabolite, Tx‐M; COX‐1 inhibition) were measured after 1 dose and 5 days of dosing. Peak inhibition of urinary metabolite excretion across 8 hours following dosing was the primary end point. Mean PGI‐M excretion was 33.7%, 55.9%, and 64.6% on day 1 and 49.4%, 65.1%, and 80.3% on day 5 (placebo, acetaminophen, and indomethacin, respectively). Acetaminophen and indomethacin inhibited PGI‐M excretion following single and multiple doses (P = .004 vs placebo). PGI‐M excretion inhibition after 1 dose was similar for indomethacin and acetaminophen, but significantly greater with indomethacin after multiple doses (P = .006). Mean Tx‐M excretion was 16.2%, 45.2%, and 86.6% on day 1 and 46.2%, 58.4%, and 92.6% on day 5 (placebo, acetaminophen, and indomethacin, respectively). Tx‐M excretion inhibition following 1 dose was reduced by acetaminophen (P ≤ .003). Indomethacin reduced Tx‐M excretion significantly more than acetaminophen and placebo after single and multiple doses (P ≤ .001). Acetaminophen and indomethacin inhibited COX‐1 and COX‐2 following a single dose, but acetaminophen was a less potent COX‐1 inhibitor than indomethacin.

LBOVI-A-3

To pilot a pharmacodynamic (PD) model of short‐term androgen administration that may be used to predict long‐term effects of androgen administration in postmenopausal women. The study was specifically designed to identify biomarkers that evaluate early skin response to exogenous androgens. The clinical consequences of androgen administration include hirsutism and acne. Skin biopsies were performed to document morphological changes in the pilosebaceous unit (PSU) and gene expression changes (Taqman and microarray). Functional skin response was gauged by measuring sebum excretion rates (SER).