Wen-Lin Luo

Niacin Lipid Efficacy Is Independent of Both the Niacin Receptor GPR109A and Free Fatty Acid Suppression

GPR109A is not the target mediating niacin’s lipid efficacy and the free fatty acid hypothesis does not explain niacin’s mechanism of action. Breaking Free of the “FFA Hypothesis” Free fatty acids (FFAs) appear in the blood plasma after a meal. Niacin—a vitamin that helps to regulate lipid levels in the body—is given to patients to reduce the amount of FFAs. It also works to raise “good” cholesterol [high-density lipoprotein (HDL)] and lower both “bad” cholesterol [low-density lipoprotein (LDL)] and triglycerides. The “FFA hypothesis” suggests that niacin works to exert these beneficial lipid effects by limiting the amount of FFAs available to synthesize triglycerides. Lauring, Taggart, and colleagues now challenge this long-standing theory. In studies in mice and humans, the authors debunk the hypothesis, showing that the effect on HDL, LDL, and triglycerides is not directly linked to FFAs. To study the lipid-modifying effects of niacin (nicotinic acid), Lauring et al. used a genetic, humanized mouse model lacking the LDL receptor. In these animals, niacin increased HDL cholesterol levels, as expected. Lack of GPR109A in these animals blocked the anti-lipolytic effect of nicotinic acid on FFAs but had no effect on drug-related changes in plasma HDL and LDL cholesterol or triglyceride levels. Treatment of the mice with a GPR109A agonist, MK-1903, also caused an anti-lipolytic effect but did not affect levels of triglyceride or LDL and HDL cholesterol. Together, these in vivo preclinical studies suggest that niacin works to lower FFAs through GPR109A but has an independent mechanism of action on other lipids. The authors addressed the role of GPR109A in humans by testing the effects of MK-1903 and of another synthetic GPR109A agonist in clinical trials. Both agonists affected FFA lipolysis but had only minor effects on HDL cholesterol and triglyceride levels in patients, thus mirroring results seen in animals and showing that niacin works independently of GPR109A to modify dyslipidemia. The studies by Lauring et al. point to a new, yet-uncovered mechanism of action for niacin’s beneficial effects on lipids in the blood. Despite overturning the FFA hypothesis and potentially redirecting drug development away from GPR109A agonists, niacin could still be useful for treating other diseases in patients, including atherosclerosis and inflammation, where GPR109A plays a major role in cell signaling. Nicotinic acid (niacin) induces beneficial changes in serum lipoproteins and has been associated with beneficial cardiovascular effects. Niacin reduces low-density lipoprotein, increases high-density lipoprotein, and decreases triglycerides. It is well established that activation of the seven-transmembrane Gi-coupled receptor GPR109A on Langerhans cells results in release of prostaglandin D2, which mediates the well-known flushing side effect of niacin. Niacin activation of GPR109A on adipocytes also mediates the transient reduction of plasma free fatty acid (FFA) levels characteristic of niacin, which has been long hypothesized to be the mechanism underlying the changes in the serum lipid profile. We tested this “FFA hypothesis” and the hypothesis that niacin lipid efficacy is mediated via GPR109A by dosing mice lacking GPR109A with niacin and testing two novel, full GPR109A agonists, MK-1903 and SCH900271, in three human clinical trials. In mice, the absence of GPR109A had no effect on niacin’s lipid efficacy despite complete abrogation of the anti-lipolytic effect. Both MK-1903 and SCH900271 lowered FFAs acutely in humans; however, neither had the expected effects on serum lipids. Chronic FFA suppression was not sustainable via GPR109A agonism with niacin, MK-1903, or SCH900271. We conclude that the GPR109A receptor does not mediate niacin’s lipid efficacy, challenging the long-standing FFA hypothesis.

Pharmacokinetics and Pharmacodynamics of Once-Daily versus Twice-Daily Raltegravir in Treatment-Naïve HIV-Infected Patients

ABSTRACT QDMRK was a phase III clinical trial of raltegravir given once daily (QD) (800-mg dose) versus twice daily (BID) (400 mg per dose), each in combination with once-daily coformulated tenofovir-emtricitabine, in treatment-naive HIV-infected patients. Pharmacokinetic (PK) and pharmacokinetic/pharmacodynamic (PK/PD) analyses were conducted using a 2-step approach: individual non-model-based PK parameters from observed sparse concentration data were determined, followed by statistical analysis of potential relationships between PK and efficacy response parameters after 48 weeks of treatment. Sparse PK sampling was performed for all patients (QD, n = 380; BID, n = 384); selected sites performed an intensive PK evaluation at week 4 (QD, n = 22; BID, n = 20). In the intensive PK subgroup, daily exposures (area under the concentration-time curve from 0 to 24 h [AUC0–24]) were similar between the two regimens, but patients on 800 mg QD experienced ∼4-fold-higher maximum drug concentration in plasma (Cmax) values and ∼6-fold-lower trough drug concentration (Ctrough) values than those on 400 mg BID. Geometric mean (GM) Ctrough values were similarly lower in the sparse PK analysis. With BID dosing, there was no indication of any significant PK/PD association over the range of tested PK parameters. With QD dosing, Ctrough values correlated with the likelihood of virologic response. Failure to achieve an HIV RNA level of <50 copies/ml appeared predominantly at high baseline HIV RNA levels in both treatment arms and was associated with lower values of GM Ctrough in the 800-mg-QD arm, though other possible drivers of efficacy, such as time above a threshold concentration, could not be evaluated due to the sparse sampling scheme. Together, these findings emphasize the importance of the shape of the plasma concentration-versus-time curve for long-term efficacy.

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 × 5 days) in the other period. The geometric mean ratios and 90% confidence intervals ([rosiglitazone + sitagliptin]/rosiglitazone) for rosiglitazone AUC0‐∞ 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.

(1aR,5aR)1a,3,5,5a-Tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (MK-1903): a potent GPR109a agonist that lowers free fatty acids in humans.

G-protein coupled receptor (GPCR) GPR109a is a molecular target for nicotinic acid and is expressed in adipocytes, spleen, and immune cells. Nicotinic acid has long been used for the treatment of dyslipidemia due to its capacity to positively affect serum lipids to a greater extent than other currently marketed drugs. We report a series of tricyclic pyrazole carboxylic acids that are potent and selective agonists of GPR109a. Compound R,R-19a (MK-1903) was advanced through preclinical studies, was well tolerated, and presented no apparent safety concerns. Compound R,R-19a was advanced into a phase 1 clinical trial and produced a robust decrease in plasma free fatty acids. On the basis of these results, R,R-19a was evaluated in a phase 2 study in humans. Because R,R-19a produced only a weak effect on serum lipids as compared with niacin, we conclude that the beneficial effects of niacin are most likely the result of an undefined GPR109a independent pathway.

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.

The effects of laropiprant, a selective prostaglandin D₂ receptor 1 antagonist, on the antiplatelet activity of clopidogrel or aspirin.

Laropiprant (LRPT) is being developed in combination with Mercks extended-release niacin (ERN) formulation for the treatment of dyslipidemia. LRPT, an antagonist of the prostaglandin PGD2 receptor DP1, reduces flushing symptoms associated with ERN. LRPT also has affinity for the thromboxane A2 receptor TP (approximately 190-fold less potent at TP compared with DP1). Aspirin and clopidogrel are two frequently used anti-clotting agents with different mechanisms of action. Since LRPT may potentially be co-administered with either one of these agents, these studies were conducted to assess the effects of steady-state LRPT on the antiplatelet activity of steady-state clopidogrel or aspirin. Bleeding time at 24 h post-dose (trough) was pre-specified as the primary pharmacodynamic endpoint in both studies. Two separate, double-blind, randomized, placebo-controlled, crossover studies evaluated the effects of multiple-dose LRPT on the pharmacodynamics of multiple-dose clopidogrel or aspirin. Healthy subjects were randomized to once-daily oral doses of LRPT 40 mg or placebo to LRTP co-administered with clopidogrel 75 mg or aspirin 81 mg for 7 days with at least a 21-day washout between treatments. In both studies, bleeding time and platelet aggregation were assessed 4 and 24 hours post-dose on Day 7. Comparability was declared if the 90% confidence interval for the estimated geometric mean ratio ([LRPT+clopidogrel]/clopidogrel alone or [LRPT+aspirin]/aspirin alone) for bleeding time at 24 hours post-dose on Day 7 was contained within (0.66, 1.50). Concomitant daily administration of LRPT 40 mg with clopidogrel 75 mg or aspirin 81 mg resulted in an approximate 4–5% increase in bleeding time at 24 hours after the last dose vs. bleeding time after treatment with clopidogrel or aspirin alone, demonstrating that the treatments had comparable effects on bleeding time. Percent inhibition of platelet aggregation was not significantly different between LRPT co-administered with clopidogrel or aspirin vs. clopidogrel or aspirin alone at 24 hours post-dose at steady state. At 4 hours after the last dose, co-administration of LRPT 40 mg resulted in 3% and 41% increase in bleeding time vs. bleeding time after treatment with aspirin or clopidogrel alone, respectively. Co-administration of LPRT with clopidogrel or aspirin was generally well tolerated in healthy subjects. Co-administration of multiple doses of LRPT 40 mg and clopidogrel 75 mg or aspirin 81 mg had no clinically important effects on bleeding time or platelet aggregation.

A comparison of the pharmacokinetics of two different formulations of extended-release niacin

ABSTRACT Objective: The objective of this study was to compare pharmacokinetic parameters of niacin extended-release tablets (NER uncoated)* and niacin extended-release caplet formation (NER coated)†. * Niaspan is a product manufactured by CF Kos Life Sciences LLC, Cranbury, NJ, USA † Niaspan CF is a product manufactured by CF Kos Life Sciences LLC, Cranbury, NJ, USA Research design and methods: Twenty-five healthy male and female subjects were enrolled in a four-period, open-label, randomized, crossover study. Both NER uncoated and NER coated were given as 1 × 1000 mg or 2 × 500 mg tablets. Similarity of NER coated 1 × 1000 mg and NER uncoated 2 × 500 mg was declared if 90% confidence intervals for the geometric mean ratio (GMR) for nicotinuric acid (NUA) Cmax fell within the pre-specified bounds of [0.7, 1.43]. Results: The GMRs for NUA Cmax demonstrated similarity in the pharmacokinetics of NER uncoated 2 × 500 mg, NER coated 1 × 1000 mg, and NER coated 2 × 500 mg. Although less stringent comparability bounds were prespecified for the primary pharmacokinetic endpoint (i.e., Cmax of plasma NUA), inspection of the primary comparison of interest indicated that a hypothesis with more stringent bioequivalence bounds of [0.8, 1.25] would have been satisfied. The NUA Cmax for NER uncoated 1 × 1000 mg was approximately 40% higher than that seen for the other three treatments. In contrast, total urinary excretion of niacin and its metabolites, an approximate measure of bioavailability, was similar for all four treatments. Conclusion: The pharmacokinetic profile of the original NER uncoated formulation dosed as 2 × 500 mg was similar to the new film-coated formulation, NER coated, dosed as 1 × 1000 mg.

The effects of laropiprant on the antiplatelet activity of co-administered clopidogrel and aspirin

Abstract Laropiprant is an antagonist of the prostaglandin PGD2 receptor DP1. Laropiprant has a weak affinity for the thromboxane A2 receptor TP. Two double-blinded, randomized, placebo-controlled, crossover studies evaluated the effects of multiple-dose laropiprant at steady state on the antiplatelet effects of multiple-dose aspirin and clopidogrel. Study 1 had two treatment periods, in which each healthy subject received laropiprant 40 mg, clopidogrel 75 mg, and aspirin 80 mg (Treatment A), or placebo, clopidogrel 75 mg, and aspirin 80 mg (Treatment B) once daily for 7 days. Study 2 consisted of three treatment periods. In the first two, each patient with hypercholesterolemia or mixed dyslipidemia received laropiprant 40 mg, clopidogrel 75 mg, and aspirin 81 mg (Treatment A), or placebo, clopidogrel 75 mg, and aspirin 81 mg (Treatment B) once daily for 7 days. In period 3, patients received a single dose of two tablets of extended release nicotinic acid 1 g/laropiprant 20 mg (Treatment C). In both studies, pharmacodynamic endpoints included bleeding time at 24 (primary) and 4 hours (secondary) post-dose following 7 days of once-daily laropiprant in combination with clopidogrel and aspirin, and platelet aggregation in platelet-rich plasma at 4 and 24 hours post-dose on day 7 (secondary). After 7 days, increased bleeding time of 27% (Study 1) and 23% (Study 2) at 24 hours post-dose was observed with laropiprant compared to placebo (both combined with clopidogrel and aspirin), with corresponding upper bounds of the 90% CI marginally exceeding the prespecified upper comparability bound of 1.50 in both studies. The GMR and 90% CI for bleeding time of laropiprant compared to placebo (both combined with clopidogrel and aspirin) at 4 hours post-dose on day 7 was 0.92 (0.70, 1.21) in Study 1, and 1.46 (1.20, 1.78) in Study 2. Compared with placebo, laropiprant (both combined with clopidogrel and aspirin) increased the inhibition of collagen- and ADP-induced platelet aggregation, respectively, by ∼2.4% and ∼8.1% in Study 1 and by ∼4% and ∼5.4% in Study 2, at 24 hours post-dose on day 7. The inhibition of collagen- and ADP-induced platelet aggregation, respectively, was increased by ∼0.1% and ∼5.0% in Study 1, and by ∼5% and ∼12% in Study 2, at 4 hours post-dose on day 7. In conclusion, co-administration of multiple doses of laropiprant with aspirin and clopidogrel induced a prolongation of bleeding time and an inhibitory effect on platelet aggregation ex vivo in healthy subjects and patients with dyslipidemia.

Single Therapeutic and Supratherapeutic Doses of Laropiprant, a Selective Prostaglandin D2 Receptor 1 Antagonist, Do Not Prolong the QTcF Interval in Healthy Volunteers

Laropiprant (LRPT), a prostaglandin D2 receptor‐1 antagonist shown to reduce niacin‐induced flushing symptoms, has been combined with niacin for treatment of dyslipidemia. This study evaluated the effects of LRPT (50 mg and 600 mg, respectively) on the QT interval with Fridericias correction (QTcF). QTcF measurements were made over a 24‐hour period following administration of single‐dose moxifloxacin 400 mg, LRPT 50 mg, LRPT 600 mg, or placebo. The primary hypothesis was supported if the 90% confidence intervals (CIs) for the least squares (LS) mean differences between placebo and LRPT in change from baseline in QTcF interval were <10 milliseconds at every time point. The upper limits of the 90% CIs for LS mean differences from placebo in changes from baseline in QTcF intervals for LRPT 50 mg and 600 mg were <5 milliseconds at every time point. The lower limits of the 90% CIs for placebo‐adjusted LS mean changes from baseline in QTcF intervals for moxifloxacin exceeded 0 milliseconds at every time point, demonstrating the sensitivity of this assay to detect increases in the QTcF interval. In conclusion, single doses of LRPT 50 mg and 600 mg do not prolong the QTcF interval relative to placebo and are generally well tolerated.

Effects of Multiple Doses of Clarithromycin on the Pharmacokinetics of Laropiprant in Healthy Subjects

Laropiprant is a selective antagonist of the prostaglandin D2 receptor subtype 1, and is primarily eliminated via glucuronidation with a minor contribution from oxidative metabolism via CYP3A. The effects of multiple oral doses of clarithromycin on the pharmacokinetics of laropiprant were investigated in an open-labeled, randomized, 2-period cross-over study. A single oral dose of 40 mg laropiprant was administered alone or coadministered with 500 mg clarithromycin b.i.d. on Day 5 of a 7-day clarithromycin regimen. Geometric mean ratios (90% confidence intervals) for AUC0-∞ and Cmax of laropiprant in the presence versus absence of clarithromycin were 1.39 (1.19, 1.62) and 1.46 (1.17, 1.80), respectively. No statistically significant differences were observed in Tmax (P= 0.543) or apparent terminal half-life (P= 0.502) of laropiprant, which implies that the effect of clarithromycin on laropiprant is largely a first-pass rather than a systemic effect. The results of this study suggest that laropiprant is not a sensitive CYP3A substrate, and strong CYP3A inhibitors like clarithromycin are not expected to have a clinically meaningful impact on the pharmacokinetics of laropiprant.