Investigation of pharmacokinetic drug interaction between clesacostat and DGAT2 inhibitor ervogastat in healthy adult participants.

Co-administration of clesacostat (acetyl-CoA carboxylase inhibitor, PF-05221304) and ervogastat (diacylglycerol O-acyltransferase inhibitor, PF-06865571) in laboratory models improved non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) end points and mitigated clesacostat-induced elevations in circulating triglycerides. Clesacostat is cleared via organic anion-transporting polypeptide-mediated hepatic uptake and cytochrome P450 family 3A (CYP3A); in vitro clesacostat is identified as a potential CYP3A time-dependent inactivator. In vitro ervogastat is identified as a substrate and potential inducer of CYP3A. Prior to longer-term efficacy trials in participants with NAFLD, safety and pharmacokinetics (PK) were evaluated in a phase I, non-randomized, open-label, fixed-sequence trial in healthy participants. In Cohort 1, participants (n = 7) received clesacostat 15 mg twice daily (b.i.d.) alone (Days 1-7) and co-administered with ervogastat 300 mg b.i.d. (Days 8-14). Mean systemic clesacostat exposures, when co-administered with ervogastat, decreased by 12% and 19%, based on maximum plasma drug concentration and area under the plasma drug concentration-time curve during the dosing interval, respectively. In Cohort 2, participants (n = 9) received ervogastat 300 mg b.i.d. alone (Days 1-7) and co-administered with clesacostat 15 mg b.i.d. (Days 8-14). There were no meaningful differences in systemic ervogastat exposures when administered alone or with clesacostat. Clesacostat 15 mg b.i.d. and ervogastat 300 mg b.i.d. co-administration was overall safe and well tolerated in healthy participants. Cumulative safety and no clinically meaningful PK drug interactions observed in this study supported co-administration of these two novel agents in additional studies exploring efficacy and safety in the management of NAFLD.

Metabolism and Excretion of Nirmatrelvir in Humans Using Quantitative Fluorine Nuclear Magnetic Resonance Spectroscopy: A Novel Approach for Accelerating Drug Development.

Typically human absorption, distribution, metabolism, and excretion (ADME) studies are executed using radiolabeled (e.g., carbon-14) material, the synthesis of which is a time-consuming activity. In this study, we were able to assess the metabolism and excretion of unlabeled nirmatrelvir (PF-07321332) within the first-in-human study via a novel application of quantitative fluorine (19 F) nuclear magnetic resonance (NMR) spectroscopy in place of a standard radiolabel ADME study. Six healthy participants received a single 300-mg oral dose of nirmatrelvir (in combination with ritonavir), and excreta were collected up to 10 days. Virtually all drug-related material was recovered within 5 days, and mass balance was achieved with 84.9 ± 8.9% (range = 70.7-95.5%) of the administered dose recovered in urine and feces. The excretion of fluorine-containing material in urine and feces was 47.0% and 33.7%, respectively. Unchanged nirmatrelvir represented 82.5% of the normalized drug-related material with a carboxylic acid metabolite M5, derived from hydrolysis of the P2 amide bond, present at 12.1% of dose. Nirmatrelvir was the only drug-related entity observed in plasma. Approximately 4.2% of the dose was excreted as metabolite M8 (measured by liquid chromatography-mass spectrometry), which was 19 F NMR silent due to hydrolysis of the trifluoroacetamide moiety. Hydrolysis of nirmatrelvir to M5 and M8 was shown to occur in cultures of human gut microflora. This successful demonstration of quantitative 19 F NMR spectroscopy to establish the mass-balance, excretion, and metabolic profile of nirmatrelvir offers an advantageous means to execute human ADME studies for fluorine-containing compounds early in drug development.

Inhibition of ketohexokinase in adults with NAFLD reduces liver fat and inflammatory markers: A randomized phase 2 trial.

BACKGROUND: Increased consumption of the lipogenic sugar fructose promotes the current epidemic of metabolic disease. Ketohexokinase (KHK) catalyzes the first committed step in fructose metabolism. In animal models, KHK inhibition decreases hepatic de novo lipogenesis and steatosis and corrects many metabolic abnormalities associated with insulin resistance. The consequences of inhibiting fructose metabolism in humans have not been tested. This randomized, double-blind, placebo-controlled, phase 2a study (NCT03256526) assessed the effect of the reversible KHK inhibitor PF-06835919 on metabolic parameters in participants with non-alcoholic fatty liver disease (NAFLD). METHODS: Adults with NAFLD (>6% whole liver fat [WLF] by magnetic resonance imaging-proton density fat fraction) received once-daily oral placebo or PF-06835919 75 mg or 300 mg for 6 weeks. Randomization (1:1:1) was via computer-generated randomization code with random permuted blocks. Endpoints included WLF (primary endpoint), safety/tolerability, and metabolic parameters. FINDINGS: Overall, 158 participants were screened and 53 randomized; 48 completed the trial (placebo, n = 17; PF-06835919 75 mg, n = 17; PF-06835919 300 mg, n = 14). Compared with placebo, significant reductions in WLF were observed in participants receiving PF-06835919 300 mg (difference of -18.73%; p = 0.04), but not with 75 mg. In addition, inhibition of KHK resulted in improvement in inflammatory markers. The incidence of treatment-emergent adverse events (AEs) was low and similar across treatment groups (26.3%, 23.5%, and 29.4% of participants in the placebo and PF-06835919 75 mg and 300 mg groups, respectively). No serious AEs were reported. CONCLUSIONS: Data suggest that KHK inhibition may be clinically beneficial in the treatment of adults with NAFLD and insulin resistance. FUNDING: This study was sponsored by Pfizer Inc.

Mini-Review: Comprehensive Drug Disposition Knowledge Generated in the Modern Human Radiolabeled ADME Study.

The human radiolabeled absorption, distribution, metabolism, and excretion (ADME) study offers a quantitative and comprehensive overall picture of the disposition of a drug, including excretion pattern and metabolite profiles in circulation and excreta. The data gathered from the ADME study are highly informative for developing a cohesive strategy for clinical pharmacology studies. Elements of standard ADME study designs are described. An exciting new development in human ADME studies is the application of accelerator mass spectrometry (AMS) as the detection technique for carbon-14, in replacement of radioactivity measurements. This technology permits administration of 100-fold to 1,000-fold lower amounts of carbon-14, and thus opens the door to the application of new study designs. A new ADME study design, termed the AMS-Enabled Human ADME study, is described. In this design, both oral and intravenous administration are assessed in a single clinical study with a two-period crossover. In addition to all of the standard ADME study end points (e.g., mass balance and quantitative metabolite profiles), the AMS-Enabled ADME study can provide the fundamental pharmacokinetic parameters of clearance, volume of distribution, absolute oral bioavailability, and even estimates of the fraction of the dose absorbed. Thus, we have entered a new era of human ADME study design that can yield vastly more informative and complete data sets enabling a superior understanding of overall drug disposition.

Efficacy and safety of the glucagon receptor antagonist PF-06291874: A 12-week, randomized, dose-response study in patients with type 2 diabetes mellitus on background metformin therapy.

AIMS: To conduct a dose-response assessment of the efficacy and safety of the glucagon receptor antagonist PF-06291874 in adults with type 2 diabetes (T2DM) using stable doses of metformin. MATERIALS AND METHODS: This randomized, double-blind, statin-stratified, placebo-controlled, 4-arm, parallel-group study was conducted in patients with T2DM who were receiving background metformin. After an 8-week, non-metformin oral antidiabetic agent washout period, 206 patients were randomized to placebo or PF-06291874 (30, 60 or 100 mg once daily) for 12 weeks. Glycosylated haemoglobin (HbA1c), fasting plasma glucose (FPG) and safety endpoints were assessed at baseline and post baseline. RESULTS: Dose-dependent mean reductions from baseline in HbA1c for PF-06291874 ranged from -0.67% (-7.29 mmol/mol) to -0.93% (-10.13 mmol/mol), and for FPG from -16.6 to -33.3 mg/dL after 12 weeks of dosing. The incidence of hypoglycaemia was low and was similar between groups receiving PF-06291874 and placebo. Small, non-dose-dependent increases in LDL cholesterol (<10%) and blood pressure (BP) (systolic BP > 2 mm Hg; diastolic BP > 1 mm Hg) were observed with PF-06291874. Modest non-dose-dependent median increases were observed across PF-06291874 groups at 12 weeks for alanine aminotransferase (range, 37.6-48.7 U/L vs placebo) and aspartate aminotransferase (range, 33.3-36.6 U/L vs placebo); these were not associated with bilirubin changes. Small increases were observed in body weight (< 0.5 kg) in each PF-06291874 group vs placebo. CONCLUSIONS: In patients with T2DM, PF-06291874 significantly lowered HbA1c and glucose, was well tolerated and carried a low risk of hypoglycaemia. Small, non-dose-related increases in BP, lipids and hepatic transaminases were observed.

Model-based development of anacetrapib, a novel cholesteryl ester transfer protein inhibitor.

A model-based strategy was used to inform the early clinical development of anacetrapib, a novel cholesteryl ester transfer protein inhibitor under development for the treatment of hyperlipidemia. The objectives of this model-based approach were to enable bridging variable pharmacokinetic effects, differences among formulations used in development, and to identify an appropriate dose for the phase III confirmatory program. Nonlinear mixed effects PK/PD models were initially developed based on data obtained from multiple phase I studies and later were updated with data from a phase IIb study. The population pharmacokinetic model described differences between the liquid-filled capsule used in phase I and phase IIb and the hot-melt extruded (HME) tablet formulation introduced in phase III, allowing for bridging of the two formulations, and quantified the complex relationship of apparent anacetrapib bioavailability with subject meal intake. Proportional E(max) models quantified the relationships between anacetrapib trough concentration and lipoprotein effects (LDL-C and HDL-C), with covariate effects of study population (normal volunteers vs. patients), and co-administration with HMG-CoA reductase inhibitor ("statin"). The interaction between anacetrapib and atorvastatin suggested pharmacological independence, i.e., that when given together, each agent exerts the same proportional lipid effect observed from monotherapy. Clinical trial simulation was used to examine the robustness of the effects to random dietary indiscretion, and found that the results were robust as long as patients generally adhered to a low-fat diet. These results allowed the selection of the 100 mg dose with the HME formulation for phase III development even though this dose and formulation were not specifically studied in a phase IIb trial.

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.

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 compound's 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 + diltiazem(XR × 5 days)/midazolam + diltiazem(XR × 2 days)) for midazolam AUC(0-∞) was 0.98 (90% confidence interval [CI], 0.87, 1.10). The GMR (midazolam + diltiazem(XR × 2 days)/midazolam + diltiazem(CR × 2 days)) for midazolam AUC(0-∞) was 0.82 (90% CI, 0.73, 0.92). Simcyp simulations accurately predicted the observed clinical results only when a hepatic CYP3A degradation rate (k(deg)) 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.

Metabolism and excretion of anacetrapib, a novel inhibitor of the cholesteryl ester transfer protein, in humans.

Anacetrapib is a novel cholesteryl ester transfer protein inhibitor being developed for the treatment of primary hypercholesterolemia and mixed dyslipidemia. The absorption, distribution, metabolism, and excretion of anacetrapib were investigated in an open-label study in which six healthy male subjects received a single oral dose of 150 mg and 165 microCi of [(14)C]anacetrapib. Plasma, urine, and fecal samples were collected at predetermined times for up to 14 days postdose and were analyzed for total radioactivity, the parent compound, and metabolites. The majority of the administered radioactivity (87%) was eliminated by fecal excretion, with negligible amounts present in urine (0.1%). The peak level of radioactivity in plasma (approximately 2 microM equivalents of [(14)C]anacetrapib) was achieved approximately 4 h postdose. The parent compound was the major radioactive component (79-94% of total radioactivity) in both plasma and feces. Three oxidative metabolites, M1, M2, and M3, were detected in plasma and feces and were identified as the O-demethylated species (M1) and two secondary hydroxylated derivatives of M1 (M2 and M3). Each metabolite was detected at low levels, representing

Single-dose pharmacokinetics and pharmacodynamics of anacetrapib, a potent cholesteryl ester transfer protein (CETP) inhibitor, in healthy subjects.

AIMS: Anacetrapib is an orally active and potent inhibitor of CETP in development for the treatment of dyslipidaemia. These studies endeavoured to establish the safety, tolerability, pharmacokinetics and pharmacodynamics of rising single doses of anacetrapib, administered in fasted or fed conditions, and to preliminarily assess the effect of food, age, gender and obesity on the single-dose pharmacokinetics and pharmacodynamics of anacetrapib. METHODS: Safety, tolerability, anacetrapib concentrations and CETP activity were evaluated. RESULTS: Anacetrapib was rapidly absorbed, with peak concentrations occurring at approximately 4 h post-dose and an apparent terminal half-life ranging from approximately 9 to 62 h in the fasted state and from approximately 42 to approximately 83 h in the fed state. Plasma AUC and C(max) appeared to increase in a less than approximately dose-dependent manner in the fasted state, with an apparent plateau in absorption at higher doses. Single doses of anacetrapib markedly and dose-dependently inhibited serum CETP activity with peak effects of approximately 90% inhibition at t(max) and approximately 58% inhibition at 24 h post-dose. An E(max) model best described the plasma anacetrapib concentration vs CETP activity relationship with an EC(50) of approximately 22 nm. Food increased exposure to anacetrapib; up to approximately two-three-fold with a low-fat meal and by up to approximately six-eight fold with a high-fat meal. Anacetrapib pharmacokinetics and pharmacodynamics were similar in elderly vs young adults, women vs men, and obese vs non-obese young adults. Anacetrapib was well tolerated and was not associated with any meaningful increase in blood pressure. CONCLUSIONS: Whereas food increased exposure to anacetrapib significantly, age, gender and obese status did not meaningfully influence anacetrapib pharmacokinetics and pharmacodynamics.

A thorough QTc study to assess the effect of sitagliptin, a DPP4 inhibitor, on ventricular repolarization in healthy subjects.

A randomized, double-blind, placebo-controlled, 4-period crossover study was performed with a single oral dose of sitagliptin (100 mg, 800 mg), moxifloxacin (400 mg), and placebo in order to provide a rigorous assessment of the effect of sitagliptin on ventricular repolarization based on the ICH E14 guidance. The clinical dose of sitagliptin 100 mg was not associated with an increase in QTc interval, corrected using the Fridericia correction (QTcf), at any time point. The supratherapeutic 800-mg dose of sitagliptin was generally well tolerated and was associated with minimal, clinically insignificant prolongation of the QTcf interval at concentrations approximately 11-fold higher than maximal concentrations following the 100-mg clinical dose. The PK/QTc model demonstrated a shallow relationship between the plasma concentration of sitagliptin and the placebo-subtracted QTcf change from baseline, with a 0.59-millisecond increase in QTc for every 1000-nM increment in sitagliptin plasma concentration. The sensitivity of the assay to detect modest increases in QTc interval was established with the active control moxifloxacin. In conclusion, at clinically relevant concentrations, sitagliptin is not associated with clinically meaningful QTcf prolongation.

Effect of moderate hepatic insufficiency on the pharmacokinetics of sitagliptin.

BACKGROUND: Sitagliptin is a highly selective dipeptidyl peptidase-4 inhibitor for the treatment of patients with type 2 diabetes. Sitagliptin is primarily excreted by renal elimination as unchanged drug, with only a small percentage (approximately 16%) undergoing hepatic metabolism. OBJECTIVES: The primary purpose of this study was to evaluate the influence of moderate hepatic insufficiency on the pharmacokinetics of sitagliptin. METHODS: In an open-label study, a single 100-mg oral dose of sitagliptin was administered to 10 male or female patients with moderate hepatic insufficiency (Child-Pugh's scores ranged from 7 to 9) and 10 healthy control subjects matched to each patient for race, gender, age (+/- 5 yrs) and body mass index (BMI kg/m2 +/- 5%). After administration of each dose, blood and urine samples were collected to assess sitagliptin pharmacokinetics. RESULTS: The mean AUC(0-infinity) and Cmax for sitagliptin were numerically, but not significantly (p>0.050), higher in patients with moderate hepatic insufficiency compared with healthy matched control subjects by 21% and 13%, respectively. These slight differences were also not considered to be clinically meaningful. Moderate hepatic insufficiency had no statistically significant effect on the Tmax, apparent terminal t(1/2), fraction of the oral dose excreted into urine (f(e,0-infinity)) and renal clearance (ClR) (p>0.100) of sitagliptin. Sitagliptin was generally well tolerated by both patients and subjects; all adverse experiences were transient and rated as mild in intensity. CONCLUSIONS: Moderate hepatic insufficiency has no clinically meaningful effect on the pharmacokinetics of sitagliptin.

Assessment of the CYP3A-mediated drug interaction potential of anacetrapib, a potent cholesteryl ester transfer protein (CETP) inhibitor, in healthy volunteers.

In this study, midazolam was used as a probe-sensitive CYP3A substrate to investigate the effect of anacetrapib on CYP3A activity, and ketoconazole was used as a probe-inhibitor to investigate the effect of potent CYP3A inhibition on the pharmacokinetics of anacetrapib, a novel cholesteryl ester transfer protein inhibitor in development for the treatment of dyslipidemia. Two partially blinded, randomized, 2-period, fixed-sequence studies were performed. Safety, tolerability, and midazolam and anacetrapib plasma concentrations were assessed. All treatments were generally well tolerated. The geometric mean ratios (90% confidence interval) of midazolam with anacetrapib/midazolam alone for AUC0-infinity and Cmax were 1.04 (0.94, 1.14) and 1.15 (0.97, 1.37), respectively. Exposure to anacetrapib was increased by ketoconazole--specifically, the geometric mean ratios (90% confidence interval) of anacetrapib with ketoconazole/anacetrapib alone for AUC0-infinity and Cmax were 4.58 (3.68, 5.71) and 2.37 (2.02, 2.78), respectively. The study showed that anacetrapib does not inhibit or induce CYP3A activity. Furthermore, anacetrapib appears to be a moderately sensitive substrate of CYP3A.

Sitagliptin, an dipeptidyl peptidase-4 inhibitor, does not alter the pharmacokinetics of the sulphonylurea, glyburide, in healthy subjects.

AIMS: Sitagliptin, a dipeptidyl peptidase-4 inhibitor, is an incretin enhancer that is approved for the treatment of Type 2 diabetes. Sitagliptin is mainly renally eliminated and not an inhibitor of CYP450 enzymes in vitro. Glyburide, a sulphonylurea, is an insulin sensitizer and mainly metabolized by CYP2C9. Since both agents may potentially be co-administered, the purpose of this study was to examine the effects of sitagliptin on glyburide pharmacokinetics. METHODS: In this open-label, randomized, two-period crossover study, eight healthy normoglycaemic subjects, 22-44 years old, received single 1.25-mg doses of glyburide alone in one period and co-administered with sitagliptin on day 5 following a multiple-dose regimen for sitagliptin (200-mg q.d. x 6 days) in the other period. RESULTS: The geometric mean ratios and 90% confidence intervals [(glyburide + sitagliptin)/glyburide] for AUC(0-infinity) and C(max) were 1.09 (0.96, 1.24) and 1.01 (0.84, 1.23), respectively. CONCLUSION: Sitagliptin does not alter the pharmacokinetics of glyburide in healthy subjects.

Effect of the cholesteryl ester transfer protein inhibitor, anacetrapib, on lipoproteins in patients with dyslipidaemia and on 24-h ambulatory blood pressure in healthy individuals: two double-blind, randomised placebo-controlled phase I studies.

BACKGROUND: The inhibition of cholesteryl ester transfer protein (CETP) is considered a potential new mechanism for treatment of dyslipidaemia. Anacetrapib (MK-0859) is a CETP inhibitor currently under development. We aimed to assess anacetrapib's effects as monotherapy on low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) and on 24-h ambulatory blood pressure. METHODS: We did two double-blind, randomised, placebo-controlled phase I studies. In the first study, 50 patients with dyslipidaemia (LDL-C 100-190 mg/dL; 40 active, 10 placebo) aged 18-75 years received anacetrapib doses of 0, 10, 40, 150, or 300 mg orally once a day with a meal for 28 days. Standard lipid and lipoprotein monitoring, safety monitoring, and anacetrapib concentrations for pharmacokinetics were done. In the second study, 22 healthy participants aged 45-75 years received either 150 mg of anacetrapib once a day or matching placebo with a meal for 10 days in each crossover period, in a randomised sequence, with at least a 14-day washout between the treatment periods. Continuous 24-h ambulatory blood pressure monitoring was done on day -1 and day 10 of each treatment period in this study. The primary or secondary endpoints of safety and tolerability were assessed in both studies by monitoring clinical adverse experiences, physical examinations, vital signs, 12-lead electrocardiogram, and laboratory safety. Analysis was per protocol. These trials are registered with ClinicalTrials.gov, number NCT00565292 and NCT00565006. FINDINGS: In the dyslipidaemia study, one patient withdrew consent and one was excluded from the data analysis for HDL-C and LDL-C because complete pre-dose measurements were not available. Anacetrapib produced dose-dependent lipid-altering effects with peak lipid-altering effects of 129% (mean 51.1 [SD 3.8]-114.9 [7.9] mg/dL) increase in HDL-C and a 38% (138.2 [11.4]-77.6 [7.9] mg/dL) decrease in LDL-C in patients with dyslipidaemia. In the 24-h ambulatory blood pressure study in healthy individuals, least squares difference between anacetrapib and placebo groups on day 10 were 0.60 (90% CI -1.54 to 2.74; p=0.634) mm Hg for systolic blood pressure and 0.47 (90% CI -0.90 to 1.84; p=0.561) mm Hg for diastolic blood pressure. INTERPRETATION: Anacetrapib seems to exhibit HDL-C increases greater than those seen with other investigational drugs in this class and LDL-C lowering effects similar to statins. Despite greater lipid-altering effects relative to other members of this class, anacetrapib seems not to increase blood pressure, suggesting that potent CETP inhibition by itself might not lead to increased blood pressure.

Transport of the dipeptidyl peptidase-4 inhibitor sitagliptin by human organic anion transporter 3, organic anion transporting polypeptide 4C1, and multidrug resistance P-glycoprotein.

Sitagliptin, a selective dipeptidyl peptidase 4 inhibitor recently approved for the treatment of type 2 diabetes, is excreted into the urine via active tubular secretion and glomerular filtration in humans. In this report, we demonstrate that sitagliptin is transported by human organic anion transporter hOAT3 (Km=162 microM), organic anion transporting polypeptide OATP4C1, and multidrug resistance (MDR) P-glycoprotein (Pgp), but not by human organic cation transporter 2 hOCT2, hOAT1, oligopeptide transporter hPEPT1, OATP2B1, and the multidrug resistance proteins MRP2 and MRP4. Our studies suggested that hOAT3, OATP4C1, and MDR1 Pgp might play a role in transporting sitagliptin into and out of renal proximal tubule cells, respectively. Sitagliptin did not inhibit hOAT1-mediated cidofovir uptake, but it showed weak inhibition of hOAT3-mediated cimetidine uptake (IC50=160 microM). hOAT3-mediated sitagliptin uptake was inhibited by probenecid, ibuprofen, furosemide, fenofibric acid, quinapril, indapamide, and cimetidine with IC50 values of 5.6, 3.7, 1.7, 2.2, 6.2, 11, and 79 microM, respectively. Sitagliptin did not inhibit Pgp-mediated transport of digoxin, verapamil, ritonavir, quinidine, and vinblastine. Cyclosporine A significantly inhibited Pgp-mediated transport of sitagliptin (IC50=1 microM). Our data indicate that sitagliptin is unlikely to be a perpetrator of drug-drug interactions with Pgp, hOAT1, or hOAT3 substrates at clinically relevant concentrations. Renal secretion of sitagliptin could be inhibited if coadministered with OAT3 inhibitors such as probenecid. However, the magnitude of interactions should be low, and the effects may not be clinically meaningful, due to the high safety margin of sitagliptin.

Metabolism and excretion of the dipeptidyl peptidase 4 inhibitor [14C]sitagliptin in humans.

The metabolism and excretion of [(14)C]sitagliptin, an orally active, potent and selective dipeptidyl peptidase 4 inhibitor, were investigated in humans after a single oral dose of 83 mg/193 muCi. 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.

Multiple-dose administration of sitagliptin, a dipeptidyl peptidase-4 inhibitor, does not alter the single-dose pharmacokinetics of rosiglitazone in healthy subjects.

Sitagliptin, a dipeptidyl peptidase-4 inhibitor, is an incretin enhancer that is approved for the treatment of type 2 diabetes. Sitagliptin is mainly renally eliminated and not a potent inhibitor of CYP450 enzymes in vitro. Rosiglitazone, a thiazolidenedione, is an insulin sensitizer and mainly metabolized by CYP2C8. Since both agents may potentially be coadministered, the purpose of this study was to examine the effects of sitagliptin on rosiglitazone pharmacokinetics. In this open-label, randomized, 2-period, crossover study, 12 healthy normoglycemic subjects, 21 to 44 years, received single 4-mg doses of rosiglitazone alone in one period and coadministered with sitagliptin on day 5 following a multiple-dose regimen for sitagliptin (200 mg once daily x 5 days) in the other period. The geometric mean ratios and 90% confidence intervals ([rosiglitazone + sitagliptin]/rosiglitazone) for rosiglitazone AUC(0-infinity) and Cmax were 0.98 (0.93, 1.02) and 0.99 (0.88, 1.12), respectively. In conclusion, sitagliptin did not alter the pharmacokinetics of rosiglitazone in healthy subjects.