Safety and efficacy of subcutaneous iscalimab (CFZ533) in two distinct populations of patients with Sjögren's disease (TWINSS): week 24 results of a randomised, double-blind, placebo-controlled, phase 2b dose-ranging study.

BACKGROUND: Sjögren's disease is a chronic autoimmune disease with an unmet need for targeted therapies. The aim of the TWINSS study is to evaluate the safety and efficacy of iscalimab, a monoclonal antibody against CD40, in patients with active Sjögren's disease. METHODS: This randomised, double-blind, placebo-controlled, phase 2b study, conducted at 71 sites in 23 countries, enrolled patients aged 18 years or older fulfilling the American College of Rheumatology/European Alliance of Associations for Rheumatology (EULAR) 2016 criteria. In the dose-ranging cohort 1, patients with a EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) score of 5 or higher and a EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) score of 5 or higher were randomly assigned (1:1:1:1) to subcutaneous iscalimab 150 mg, 300 mg, 600 mg, or placebo. In the proof-of-concept cohort 2, patients with an ESSDAI score of less than 5, ESSPRI (dryness or fatigue) score of 5 or higher, and Impact of Dry Eye on Everyday Life score of 30 or higher were randomly assigned (1:1) to iscalimab 600 mg or placebo. The sponsor, investigator, site personnel, and patients were masked to the treatment assignment. The primary objectives were to demonstrate a dose-response relationship of iscalimab based on the change in ESSDAI from baseline to week 24 in cohort 1 by Multiple Comparison Procedure-Modelling (MCP-Mod), and to assess the effect of iscalimab 600 mg on ESSPRI at week 24 in cohort 2. All the efficacy analyses included all patients who were randomly assigned, and safety analysis included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov (NCT03905525), and is complete. FINDINGS: Between Oct 1, 2019, and Feb 28, 2022, 460 patients were screened; 173 patients were assigned to cohort 1 (44 to iscalimab 150 mg, 43 to 300 mg, 43 to 600 mg, and 43 to placebo) and 100 to cohort 2 (50 to each group). In cohort 1, the MCP step showed a significant dose-response relationship for placebo-adjusted ESSDAI change from baseline in one of four models (Linlog model, one-sided p=0·0041). ESSDAI decreased from baseline to week 24 with all three doses of iscalimab; 150 mg and 600 mg doses showed statistically significant improvement (placebo-adjusted least squares [LS] mean difference -3·0 [95% CI -4·9 to -1·1]; p=0·0025 for 150 mg and -2·9 [-4·9 to -1·0]; p=0·0037 for 600 mg). In cohort 2, ESSPRI showed a trend towards improvement with iscalimab 600 mg (placebo-adjusted LS mean change from baseline -0·57 points [95% CI -1·30 to 0·15]; p=0·12). Serious adverse events were reported in nine patients in cohort 1 (one [2%] of 43 in the placebo group, one [2%] of 44 in the iscalimab 150 mg group, three [7%] of 42 in the 300 mg group, four [9%] of 44 in the 600 mg group) and four patients in cohort 2 (two [4%] of 50 in each group). No deaths occurred over the 24-week period. INTERPRETATION: The study met the primary objective of demonstrating a significant dose-response relationship with iscalimab in terms of disease activity at week 24. Iscalimab was well tolerated and showed initial clinical benefit over placebo in two distinct populations of patients with Sjögren's disease, to be confirmed in larger trials. FUNDING: Novartis Pharma.

Mechanically Adaptive Polymers Constructed from Dynamic Coordination Equilibria.

Designing materials capable of adapting their mechanical properties in response to external stimuli is the key to preventing failure and extending their service life. However, existing mechanically adaptive polymers are hindered by limitations such as inadequate load-bearing capacity, difficulty in achieving reversible changes, high cost, and a lack of multiple responsiveness. Herein, we address these challenges using dynamic coordination bonds. A new type of mechanically adaptive material with both rate- and temperature-responsiveness was developed. Owing to the stimuli-responsiveness of the coordination equilibria, the prepared polymers, PBMBD-Fe and PBMBD-Co, exhibit mechanically adaptive properties, including temperature-sensitive strength modulation and rate-dependent impact hardening. Benefitting from the dynamic nature of the coordination bonds, the polymers exhibited impressive energy dissipation, damping capacity (loss factors of 1.15 and 2.09 at 1.0 Hz), self-healing, and 3D printing abilities, offering durable and customizable impact resistance and protective performance. The development of impact-resistant materials with comprehensive properties has potential applications in the sustainable and intelligent protection fields.

Safety and efficacy of subcutaneous ianalumab (VAY736) in patients with primary Sjögren's syndrome: a randomised, double-blind, placebo-controlled, phase 2b dose-finding trial.

BACKGROUND: Sjögren's syndrome is an autoimmune disease characterised by dry eyes and mouth, systemic features, and reduced quality of life. There are no disease-modifying treatments. A new biologic, ianalumab (VAY736), with two modes of suppressing B cells, has previously shown preliminary efficacy. This dose-finding trial aimed to assess the safety and efficacy of different subcutaneous doses of ianalumab in patients with moderate to severe primary Sjögren's syndrome. METHODS: VAY736A2201 was a randomised, parallel, double-blind, placebo-controlled, phase 2b dose-finding study done in 56 centres in 19 countries. Patients aged 18-75 years with primary Sjögren's syndrome with moderate to severe disease activity (European Alliance of Associations for Rheumatology [EULAR] Sjögren's Syndrome Disease Activity Index [ESSDAI] score ≥6) and symptom severity (EULAR Sjögren's Syndrome Patient Reported Index score ≥5) were eligible. Participants were randomly assigned (1:1:1:1) to receive subcutaneous placebo or ianalumab (5 mg, 50 mg, or 300 mg) every 4 weeks for 24 weeks using a secure, online randomisation system. Randomisation was stratified by the ESSDAI score at baseline (≥10 or <10). Study personnel and patients were masked to treatment assignment. The primary outcome was the change in ESSDAI score from baseline to 24 weeks in all randomly assigned patients. Dose-related change in disease activity (ESSDAI) from baseline at week 24 was assessed by multiple comparison procedure with modelling analysis. Safety was measured in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT02962895. FINDINGS: Between June 27, 2017, and Dec 06, 2018, 293 patients were screened, 190 of whom were randomly assigned (placebo n=49, ianalumab 5 mg n=47, ianalumab 50 mg n=47, ianalumab 300 mg n=47). Statistically significant dose-responses were seen for overall disease activity (ESSDAI score) in four of the five dose-response models tested (p<0·025 in four models, p=0·060 in one model). The ESSDAI score decreased from baseline in all ianalumab groups, with the maximal ESSDAI score change from baseline observed in the ianalumab 300 mg group: placebo-adjusted least-squares mean change from baseline -1·92 points (95% CI -4·15 to 0·32; p=0·092). There were four serious adverse events in three patients considered treatment-related (pneumonia [n=1] and gastroenteritis [n=1] in the placebo group; appendicitis plus tubo-ovarian abscess in the same patient in the ianalumab 50 mg group). INTERPRETATION: The study met its primary objective, showing a dose-related decrease in disease activity as measured by ESSDAI at week 24. Overall, ianalumab was well tolerated and safe, with no increase in infections. To our knowledge, this is the first large, randomised, controlled trial in primary Sjögren's syndrome that met its primary endpoint, and its results mean there is potential for more studies of this mechanism in the future. FUNDING: Novartis.

Improving the assessment of the probability of success in late stage drug development.

There are several steps to confirming the safety and efficacy of a new medicine. A sequence of trials, each with its own objectives, is usually required. Quantitative risk metrics can be useful for informing decisions about whether a medicine should transition from one stage of development to the next. To obtain an estimate of the probability of regulatory approval, pharmaceutical companies may start with industry-wide success rates and then apply to these subjective adjustments to reflect program-specific information. However, this approach lacks transparency and fails to make full use of data from previous clinical trials. We describe a quantitative Bayesian approach for calculating the probability of success (PoS) at the end of phase II which incorporates internal clinical data from one or more phase IIb studies, industry-wide success rates, and expert opinion or external data if needed. Using an example, we illustrate how PoS can be calculated accounting for differences between the phase II data and future phase III trials, and discuss how the methods can be extended to accommodate accelerated drug development pathways.

Eliciting judgements about dependent quantities of interest: The SHeffield ELicitation Framework extension and copula methods illustrated using an asthma case study.

Pharmaceutical companies regularly need to make decisions about drug development programs based on the limited knowledge from early stage clinical trials. In this situation, eliciting the judgements of experts is an attractive approach for synthesising evidence on the unknown quantities of interest. When calculating the probability of success for a drug development program, multiple quantities of interest-such as the effect of a drug on different endpoints-should not be treated as unrelated. We discuss two approaches for establishing a multivariate distribution for several related quantities within the SHeffield ELicitation Framework (SHELF). The first approach elicits experts' judgements about a quantity of interest conditional on knowledge about another one. For the second approach, we first elicit marginal distributions for each quantity of interest. Then, for each pair of quantities, we elicit the concordance probability that both lie on the same side of their respective elicited medians. This allows us to specify a copula to obtain the joint distribution of the quantities of interest. We show how these approaches were used in an elicitation workshop that was performed to assess the probability of success of the registrational program of an asthma drug. The judgements of the experts, which were obtained prior to completion of the pivotal studies, were well aligned with the final trial results.

A randomized clinical trial to evaluate the single-dose pharmacokinetics, pharmacodynamics, and safety of sitagliptin in pediatric patients with type 2 diabetes.

OBJECTIVE: To evaluate the single-dose pharmacokinetics (PK), pharmacodynamics (PD), and safety of sitagliptin in pediatric patients with type 2 diabetes mellitus (T2DM). STUDY DESIGN: This was a randomized, placebo-controlled, double-blind evaluation of sitagliptin in 35 patients 10 to 17 years old with T2DM at 7 clinical research sites. The safety, tolerability, PK, and PD (dipeptidyl peptidase-4 [DPP-4] inhibition and aspects of glucose metabolism) of single doses of 50, 100, and 200 mg were assessed. Appropriate transformations on the PK parameters were used and back-transformed summary statistics are reported. RESULTS: Adverse experiences were reported by eight study participants; all were of mild intensity except one (intravenous site pain of moderate intensity). PK characteristics in the young patients were comparable to reference adult data, with geometric mean ratios (youths/adults) for AUC0-∞ , Cmax , and C24hr of 0.82, 1.04, and 0.74, respectively. Single doses of 50, 100, and 200 mg sitagliptin inhibited 67.2%, 73.8%, and 81.2% of plasma DPP-4 activity over 24 hours, respectively. Least squares (LS) mean glucose concentrations 2 hours after an oral glucose tolerance test or a meal tolerance test decreased in study participants treated with sitagliptin, compared to placebo, while active LS mean glucagon-like peptide 1 concentrations increased significantly at all sitagliptin doses in both tests. CONCLUSIONS: Single doses of sitagliptin as high as 200 mg were generally well tolerated in 10- to 17-year-old male and female study participants with T2DM, and a daily sitagliptin dose of 100 mg is appropriate for evaluation in Phase III safety and efficacy studies in pediatric patients with T2DM. (ClinicalTrials.gov: NCT00730275).

Everolimus with Reduced Calcineurin Inhibitor Exposure in Renal Transplantation.

Background Everolimus permits reduced calcineurin inhibitor (CNI) exposure, but the efficacy and safety outcomes of this treatment after kidney transplant require confirmation.Methods In a multicenter noninferiority trial, we randomized 2037 de novo kidney transplant recipients to receive, in combination with induction therapy and corticosteroids, everolimus with reduced-exposure CNI (everolimus arm) or mycophenolic acid (MPA) with standard-exposure CNI (MPA arm). The primary end point was treated biopsy-proven acute rejection or eGFR<50 ml/min per 1.73 m2 at post-transplant month 12 using a 10% noninferiority margin.Results In the intent-to-treat population (everolimus n=1022, MPA n=1015), the primary end point incidence was 48.2% (493) with everolimus and 45.1% (457) with MPA (difference 3.2%; 95% confidence interval, -1.3% to 7.6%). Similar between-treatment differences in incidence were observed in the subgroups of patients who received tacrolimus or cyclosporine. Treated biopsy-proven acute rejection, graft loss, or death at post-transplant month 12 occurred in 14.9% and 12.5% of patients treated with everolimus and MPA, respectively (difference 2.3%; 95% confidence interval, -1.7% to 6.4%). De novo donor-specific antibody incidence at 12 months and antibody-mediated rejection rate did not differ between arms. Cytomegalovirus (3.6% versus 13.3%) and BK virus infections (4.3% versus 8.0%) were less frequent in the everolimus arm than in the MPA arm. Overall, 23.0% and 11.9% of patients treated with everolimus and MPA, respectively, discontinued the study drug because of adverse events.Conclusions In kidney transplant recipients at mild-to-moderate immunologic risk, everolimus was noninferior to MPA for a binary composite end point assessing immunosuppressive efficacy and preservation of graft function.

Validation of 4ß-hydroxycholesterol and evaluation of other endogenous biomarkers for the assessment of CYP3A activity in healthy subjects.

AIMS: This study aimed to assess changes in the plasma concentrationss of 4ß-hydroxycholesterol (4ßHC) against intravenous (i.v.) and oral midazolam (MDZ) pharmacokinetics (PK) after administration of a potent CYP3A inhibitor [ketoconazole (KETO)] and inducer [rifampicin (RIF)]. METHODS: Thirty-two healthy subjects (HS) were allocated into three groups of 12 each in KETO and RIF and 10 in a placebo group (PLB). All HS were randomized to receive oral and i.v. MDZ on day 1 or 2 and on day 15 or 16 after receiving RIF (600 mg once daily), KETO (400 mg once daily) or PLB for 2 weeks. Subjects were followed until day 30. The effect of treatments on 4ßHC was assessed by analyzing % change from baseline using a linear spline mixed effects model. RESULTS: Compared with PLB, KETO decreased 4ßHC mean values up to 13% (P = 0.003) and RIF increased 4ßHC mean values up to 220% (P < 0.001). Within 14 days of stopping KETO and RIF, 4ßHC had either returned to baseline (KETO) or was still returning to baseline (RIF). Compared with baseline, mean oral MDZ AUC increased by 11-fold (90% CI ranging from 9-fold to 13-fold increase) and decreased by 92% (90% CI ranging from 90% to 95% decrease) after KETO and RIF, respectively. Similar trends were observed for 6ß-hydroxycortisol : cortisol (6ßHCL : CL) urinary ratios. CONCLUSIONS: Changes in plasma 4ßHC can be utilized as a surrogate for MDZ PK after multiple doses of potent CYP3A inducers. There is a more limited dynamic range for 4ßHC for assessment of potential CYP3A inhibitors. 4ßHC is a valuable tool for the assessment of potential CYP3A inducers in early drug development.

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

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.

Pharmacokinetics and pharmacodynamics of once-daily versus twice-daily raltegravir in treatment-naive HIV-infected patients.

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 [AUC(0-24)]) were similar between the two regimens, but patients on 800 mg QD experienced ~4-fold-higher maximum drug concentration in plasma (C(max)) values and ~6-fold-lower trough drug concentration (C(trough)) values than those on 400 mg BID. Geometric mean (GM) C(trough) 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, C(trough) 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 C(trough) 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.

A New Comprehensive Approach to Assess the Probability of Success of Development Programs Before Pivotal Trials.

The point at which clinical development programs transition from early phase to pivotal trials is a critical milestone. Substantial uncertainty about the outcome of pivotal trials may remain even after seeing positive early phase data, and companies may need to make difficult prioritization decisions for their portfolio. The probability of success (PoS) of a program, a single number expressed as a percentage reflecting the multitude of risks that may influence the final program outcome, is a key decision-making tool. Despite its importance, companies often rely on crude industry benchmarks that may be "adjusted" by experts based on undocumented criteria and which are typically misaligned with the definition of success used to drive commercial forecasts, leading to overly optimistic expected net present value calculations. We developed a new framework to assess the PoS of a program before pivotal trials begin. Our definition of success encompasses the successful outcome of pivotal trials, regulatory approval and meeting the requirements for market access as outlined in the target product profile. The proposed approach is organized in four steps and uses an innovative Bayesian approach to synthesize all relevant evidence. The new PoS framework is systematic and transparent. It will help organizations to make more informed decisions. In this paper, we outline the rationale and elaborate on the structure of the proposed framework, provide examples, and discuss the benefits and challenges associated with its adoption.

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 Merck's 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.

Pharmacokinetics of laropiprant and glucuronide metabolite in patients with severe renal insufficiency.

Flushing symptoms limit the use of niacin as an effective treatment for dyslipidemia; laropiprant, a prostaglandin D2 receptor subtype 1 antagonist, reduces niacin-induced flushing and is being developed in combination with niacin. The aims of this study were to both determine the effect of renal insufficiency on plasma pharmacokinetics of laropiprant and to assess safety and tolerability in patients with severe renal insufficiency. This open-label study compared the pharmacokinetics of a single laropiprant 40-mg dose in 8 nondialyzed, severe renal insufficiency patients (RIs) with healthy matched subjects (HSs) (24-hour creatinine clearance <30 mL/min/1.73 m(2) and >80 mL/min/1.73 m(2) for RIs and HSs, respectively). In RIs, laropiprant was well tolerated and the area under the concentration time curve (AUC(0-infinity)) was modestly higher (ratio of geometric least-squares means [GMR] for RIs to HSs was 1.58; 90% confidence interval [CI], 1.06-2.35); neither the maximum laropiprant plasma concentration (C(max)) nor the time to C(max) (T(max)) was significantly affected. The apparent terminal half-life (t(1/2)) was 26.0 and 14.8 hours for RIs and HSs, respectively (P = 0.007). Similarly, for the inactive laropiprant glucuronide metabolite, the GMR for AUC(0-infinity) was 2.17 (90% CI, 1.44-3.27), and the apparent t(1/2) values were 25.3 to 14.5 hours (P = 0.037) in RIs and HSs, respectively. Renal insufficiency had no clinically significant effect on laropiprant pharmacokinetics. Because niacin and its metabolites are excreted through the kidneys, the combination of niacin with laropiprant should be used with caution in patients with renal impairment.

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.

On the Use of Group Sequential Study Designs for the Test of Bioequivalence for Complicated Products.

A novel modeling approach together with a use of group sequential study design for a complicated triple fixed-dose combination was attempted. Probability of success (POS) was used for determining a weighted average power, where weight was based on available information such as data from previous pilot studies or literature. A simulation study was conducted that resulted in the development of the necessary sample size for the studies in addition to identifying a decision algorithm that was prospectively defined in the protocols. Prospective inclusion of decision algorithms in the respective protocols facilitated a decision analytic approach to continuance or discontinuance of the product concept. Whereas the data suggested going to stage 2 was appropriate, the overall POS of meeting the equivalence requirements upon completion of the study were very low, leading to termination of the selected formulation concepts. The use of such novel designs for bioequivalence assessment can be applied for staged investments, particularly when there is uncertainty in formulation POS or when the pilot-scale pharmacokinetic studies are not likely to predict the final-scale pivotal studies.

Single-dose pharmacokinetics and safety of daclatasvir in subjects with renal function impairment.

BACKGROUND: Daclatasvir (DCV) is a pangenotypic inhibitor of the HCV NS5A replication complex approved in Japan and Europe for combination treatment of HCV. AI444-063 was an open-label, two-stage, adaptive study assessing DCV pharmacokinetics and safety in HCV-uninfected subjects with renal impairment. METHODS: Stage 1 included 12 subjects with end-stage renal disease (ESRD) on dialysis and 12 healthy controls (creatinine clearance [CLcr]≥90 ml/min, Cockcroft-Gault) matched by sex, age and weight. All participants received a single DCV 60-mg dose on day 1. DCV plasma levels were measured through day 4. Prespecified criteria for study expansion (ESRD versus control area under the curve extrapolated to infinite time [AUC∞] geometric mean ratio [GMR] upper 90% CI>1.5) were met; therefore, 12 subjects with moderate or severe renal impairment (estimated glomerular filtration rate, 30-59 and 15-29 ml/min/1.73m(2), respectively) were included in stage 2. RESULTS: All 36 participants (30 male, mean age 54 years) completed the study. DCV AUC∞ was higher in ESRD subjects versus controls (GMR 1.264, 90% CI 0.989, 1.616). Compared with normal CLcr (90 ml/min), GMR and 90% CI for unbound DCV AUC∞ at CLcr 60, 30 and 15 ml/min were 1.18 (1.07, 1.30), 1.39 (1.14, 1.70) and 1.51 (1.18, 1.94), respectively. DCV was generally well tolerated in subjects with normal renal function, ESRD, or moderate or severe renal impairment. CONCLUSIONS: Observed DCV exposure increases were within the normal range of variability and were not associated with an elevated risk of adverse events. DCV can be administered in subjects with renal impairment, including ESRD, without dose modification. ClinicalTrials.gov NCT01830205.

Evaluation of drug-drug interaction between daclatasvir and methadone or buprenorphine/naloxone.

INTRODUCTION: Daclatasvir (DCV) is a potent hepatitis C virus (HCV) NS5A replication complex inhibitor with pangenotypic (1-6) activity in vitro. Methadone (MET) and buprenorphine (BUP) are opioid medications used to treat opioid addiction; patients on HCV therapy may require MET or BUP treatment. The effect of DCV on the pharmacokinetics (PK) of MET or BUP/naloxone (NLX) was assessed in subjects on stable MET or BUP. MATERIALS AND METHODS: An open-label, two-part study assessed the effect of steady-state oral administration of DCV on the PK of MET (Part 1, P1) or BUP/NAL (Part 2, P2). Safety/tolerability and pharmacodynamics (PD, opioid withdrawal scales/overdose assessment) were also assessed. Subjects (P1, N=14; P2, N=11) received daily single-dose oral MET (40-120mg) or BUP/NLX (8/2-24/6mg) based on their prescribed stable dose throughout, in addition to DCV (60mg QD) on Days 2-9. Serial PK sampling occurred predose and postdose till 24 hours on Day 1 (MET/BUP) and Day 10 (MET/BUP/DCV). Noncompartmental PK were derived. Geometric mean ratios (GMR) and 90% confidence intervals (90% CI) for MET/BUP/norBUP Cmax and AUCTAU were derived from linear mixed effects models. RESULTS: Subjects were aged 19-39 years, mostly white (P1, 93%; P2, 100%) and male (P1, 71%; P2, 91%). All subjects completed the study. No clinically meaningful effect was demonstrated as the GMR and 90% CIs fell within the prespecified interval (P1, 0.7-1.4; P2, 0.5-2.0: see Table 1). DCV coadministration was well-tolerated: overall, six (43%) subjects had adverse events (AEs) (all mild and resolved without treatment). DCV had no clinically significant effect on the PD of MET or BUP/NLX. CONCLUSIONS: Steady-state administration of DCV 60mg QD had no clinically meaningful effect on the PK of MET or BUP/NLX and was generally well-tolerated, suggesting that no dose adjustments will be required.

The effects of simvastatin on the pharmacokinectics of sitagliptin.

BACKGROUND: Treatment with the combination of sitagliptin (a dipeptidyl peptidase 4 inhibitor which improves glycemic control) and simvastatin (a well characterized lipid-lowering agent) may be considered an appropriate approach to management of type 2 diabetes and its associated increased risk of cardiovascular disease. OBJECTIVE: An investigation of the effects of simvastatin on the pharmacokinetics of sitagliptin was conducted. METHODS: Ten healthy men and women were enrolled into an open-label, randomized, 2-period, crossover study. Pharmacokinetics of sitagliptin were measured after a single dose of sitagliptin 100-mg alone, and after a single dose of sitagliptin 100-mg administered on Day 5 of a 7 day course of simvastatin 80-mg once daily. RESULTS: The geometric mean ratio of (sitagliptin + simvastatin) / sitagliptin and corresponding 90% confidence interval for sitagliptin AUC0-∞ and Cmax were 1.01 (0.97, 1.05), and 1.12 (1.00, 1.26), respectively. CONCLUSIONS: Simvastatin has no clinically important effect on sitagliptin pharmacokinetics. No dose adjustment for either sitagliptin or simvastatin is recommended when these drugs are coadministered.

(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.