Pharmacokinetics, safety, and tolerability of QAW039 (fevipiprant), a novel CRTh2 receptor antagonist: Results from two randomized, phase I, placebo-controlled studies in healthy volunteers

We evaluated the pharmacokinetics (PK), safety and tolerability of a novel oral CRTh2 antagonist, QAW039 (fevipiprant); in healthy subjects. QAW039 peak concentrations in plasma were observed 1‒3 hours post-dosing. Concentrations declined in a multi-exponential manner, followed by an apparent terminal phase (t1/2 ~ 20 hours). Steady state was achieved in 4 days with < 2-fold accumulation. Elimination was partly by renal excretion (≤ 30% of the dose) and glucuronidation. Food had minimal impact on the PK of QAW039 and it was well tolerated at single and multiple oral doses up to 500 mg/day. No dose dependent adverse events were observed and all the events were mild or moderate in severity. Systemic concentrations were sufficiently high to achieve relevant target occupancy, considering in vitro pharmacology data. In summary, the data support further development as a once-daily oral therapy for allergic diseases

Pharmacokinetics, safety, and tolerability of siponimod (BAF312) in subjects with severe renal impairment: A single-dose, open-label, parallel-group study

Objective To investigate the pharmacokinetics (PK), safety, and tolerability of siponimod and selected metabolites (M3 and M5) in subjects with varying degrees of renal impairment (RI) compared to demographically matched healthy subjects (HS). Methods The study enrolled subjects with severe RI (n=8) and matched HS (n=8). Subjects with moderate and mild RI were to be enrolled only if interim analysis showed ≥50% increase in maximum plasma concentration (Cmax) or area under the curve (AUC) of total and/or unbound siponimod in severe RI subjects versus HS. All subjects received single oral dose of siponimod 0.25 mg on Day 1; PK and safety were evaluated during the follow-up (~13 days). Results PK of siponimod was marginally affected in severe RI subjects versus HS: Cmax decreased by 8% and AUClast and AUCinf increased by 23% and 24%, respectively. Siponimod plasma unbound (u) fraction was 7% higher in the severe RI subjects versus HS. Cmax(u) was comparable while AUClast(u) and AUCinf(u) increased by 32% and 33%, respectively, compared to HS. M3 exposure was similar (Cmax decreased by 9%; AUClast and AUCinf increased by 11%) and M5 exposure was slightly lower (Cmax decreased by 26%; AUClast decreased by 16%) in subjects with severe renal impairment compared with matched HS. No adverse events were reported during this study. Conclusions Changes in the plasma exposure of total and unbound siponimod and metabolites M3 and M5 were not considered to be clinically relevant. Further investigation of PK in subjects with mild and moderate RI was not warranted

George Tucker photograph, Southsea Clarence Pier, 1951.

Juvenile Circular Railway photographed 28 July 1951

Effect of mavoglurant (AFQ056) on the pharmacokinetics of a combined oral contraceptive containing ethinyl estradiol and levonorgestrel in healthy women

Objective: To compare the pharmacokinetics (PKs) of a combination oral contraceptive (OC) when given alone or concomitantly with the selective metabotropic glutamate receptor 5 antagonist mavoglurant (AFQ056). Methods: This open-label, fixed-sequence, two-period study included 30 healthy female subjects aged 18–40 years. In Period 1, a single oral dose of an OC containing 30 μg ethinyl estradiol (EE)/150 μg levonorgestrel (LNG) was administered alone. In Period 2, OC was administered with a clinically relevant multiple-dose of 100 mg b.i.d. mavoglurant under-steady conditions. Plasma concentrations of EE and LNG were measured up to 72 hours post administration and PK parameters Cmax and AUClast were estimated using noncompartmental methods. Results: The geometric mean ratios of EE PK parameters Cmax and AUClast obtained with and without mavoglurant were 0.97 (90% confidence interval [CI]: 0.90-1.06) and 0.94 (90% CI: 0.86-1.03), respectively. The corresponding Cmax and AUClast for LNG were 0.81 (90% CI: 0.75-0.87) and 0.68 (90% CI: 0.63 0.73), respectively. Conclusions: In conclusion, the EE PK was unchanged, whereas Cmax and AUClast of LNG was approximately 19% and 32% lower, respectively, when given with mavoglurant. Further investigation regarding the impact on contraceptive efficacy is warranted

Pharmacokinetic drug-drug interaction assessment of LCZ696 (an angiotensin receptor neprilysin inhibitor) with omeprazole, metformin or levonorgestrel-ethinyl estradiol in healthy subjects

LCZ696 is a novel angiotensin receptor neprilysin inhibitor in development for the treatment of cardiovascular diseases. Here, we assessed the potential for pharmacokinetic drug-drug interaction of LCZ696 (400mg, single dose or once daily [q.d.]) when co-administered with omeprazole 40mg q.d. (n=28) or metformin 1000mg q.d. (n=27) or levonorgestrel-ethinyl estradiol 150/30μg single dose (n=24) in three separate open-label, single-sequence studies in healthy subjects. Pharmacokinetic parameters of LCZ696 analytes (sacubitril, LBQ657, and valsartan), metformin, and levonorgestrel-ethinyl estradiol were assessed. Omeprazole did not alter the AUCinf of sacubitril and pharmacokinetics of LBQ657; however, 7% decrease in the Cmax of sacubitril, and 11% and 13% decreases in AUCinf and Cmax of valsartan were observed. Co-administration of LCZ696 with metformin had no significant effect on the pharmacokinetics of LBQ657 and valsartan; however, AUCtau,ss and Cmax,ss of metformin were decreased by 23%. Co-administration of LCZ696 with levonorgestrel-ethinyl estradiol had no effect on the pharmacokinetics of ethinyl estradiol and LBQ657 or AUCinf of levonorgestrel. The Cmax of levonorgestrel decreased by 15%, and AUCtau,ss and Cmax,ss of valsartan decreased by 14% and 16%, respectively. Co-administration of LCZ696 with omeprazole, metformin, or levonorgestrel-ethinyl estradiol was not associated with any clinically relevant pharmacokinetic drug interactions

Bimagrumab improves body composition and insulin sensitivity in insulin-resistant subjects

Background: Skeletal muscle is a key mediator of insulin resistance. Bimagrumab, an antibody against activin receptor type II (ActRII), prevents binding of negative muscle regulators, like myostatin, and increases lean mass and decreases fat mass in animal models. Objective: We hypothesized that an improving body composition in insulin resistant individuals could enhance insulin sensitivity. Methods: Sixteen individuals with mean body mass index (BMI)=29.3 kg/m2 and insulin resistance, received a single dose of bimagrumab or placebo and were assessed at Week 10 for insulin sensitivity, with hyperinsulinemic euglycemic (H-E) clamp and intravenous glucose tolerance test (IVGTT), and for body composition, with dual energy X-ray absorptiometry (DXA) and Positron emission tomography (PET) scan. Results: Bimagrumab increased lean mass by 2.7% (p<0.05) and reduced fat mass by 7.9% (p=0.011) at Week 10 compared to placebo, with a neutral effect on body weight. Bimagrumab reduced HbA1c by 0.21% at Week 18 (p<0.001) and improved insulin sensitivity by ~20% (using the clamp) to ~40% (using the IVGTT). Conclusion: Taken the observed changes together and in consideration that these occurred without accompanying dietary intervention and without any prescribed regular physical exercise, bimagrumab may offer a novel approach for the treatment of metabolic complications of obesity