Metabolism and Pharmacokinetic Drug-Drug Interaction Profile of Vericiguat, A Soluble Guanylate Cyclase Stimulator: Results From Preclinical and Phase I Healthy Volunteer Studies.

BACKGROUND: Vericiguat is a stimulator of soluble guanylate cyclase currently under investigation as a first-in-class therapy for worsening chronic heart failure (NCT02861534). Patients with heart failure often require polypharmacy because of comorbidities. Hence, understanding the clearance mechanisms, elimination, and potential for pharmacokinetic drug-drug interactions of vericiguat is important for dose recommendations in this patient population. METHODS: Biotransformation and perpetrator properties of vericiguat were characterized in vitro using human hepatocytes, liver microsomes, and recombinant enzymes. This was complemented by a human mass balance study and ten drug-drug interaction studies in healthy volunteers wherein vericiguat was co-administered orally with omeprazole, magnesium/aluminum hydroxide, ketoconazole, rifampicin, mefenamic acid, midazolam, warfarin, digoxin, sacubitril/valsartan, aspirin, or sildenafil. RESULTS: In the human mass balance study, mean total radioactivity recovered was 98.3% of the dose administered (53.1% and 45.2% excreted via urine and feces, respectively). The main metabolic pathway of vericiguat is glucuronidation via uridine diphosphate-glucuronosyltransferase 1A9 and 1A1. In vitro studies revealed a low risk of vericiguat acting as a perpetrator by inhibiting cytochrome P450s, uridine diphosphate-glucuronosyltransferase isoforms, or major transport proteins, or by inducing cytochrome P450s. These observations were supported by phase I drug-drug interaction studies. Phase I studies that assessed the propensity of vericiguat as a victim drug showed changes in the range that did not warrant recommendations for dose adjustment in phase III. CONCLUSIONS: A low pharmacokinetic interaction potential of vericiguat was estimated from in vitro data and confirmed in vivo. Thus, vericiguat is suitable for a patient population with multiple comorbidities requiring polypharmacy.

Phase I trial to investigate the safety, pharmacokinetics and efficacy of sorafenib combined with docetaxel in patients with advanced refractory solid tumours.

AIM: The safety, pharmacokinetics and efficacy of sorafenib plus docetaxel in patients with advanced refractory cancer were investigated in a phase I, dose-escalation trial. METHODS: Twenty-seven patients in four cohorts received docetaxel on day 1 (cohorts 1 and 4: 75 mg/m2; cohorts 2 and 3: 100 mg/m2) plus sorafenib on days 2-19 (cohorts 1 and 2: 200 mg twice-daily (bid); cohorts 3 and 4: 400 mg bid) in 21-day cycles. RESULTS: Most common adverse events (AEs) (grade 3-5) included neutropenia (89%), leucopaenia (81%), hand-foot skin reaction (30%) and fatigue (30%). The most common drug-related AEs leading to dose reduction/interruption or permanent discontinuation were dermatologic (41%), gastrointestinal (26%) and constitutional (22%). Coadministration of sorafenib altered the pharmacokinetics of docetaxel. On average, docetaxel area under the concentration-time curve (AUC)(0-24) increased by 5% (cohort 1), 54% (cohort 2), 36% (Cohort 3) and 80% (cohort 4) with docetaxel plus sorafenib, while C(max) increased by 16-32%, independent of sorafenib/docetaxel doses. Three of 25 evaluable patients (11%) had partial responses; 14 (52%) had stable disease. CONCLUSION: Dose-limiting dermatologic AEs were more common than expected for either therapy alone. A starting dose of docetaxel 75 mg/m2 plus sorafenib 400mg bid (with dose reductions for dermatological toxicities) is proposed for phase II.

Cr(VI)/Cr(III) and As(V)/As(III) ratio assessments in Jordanian spent oil shale produced by aerobic combustion and Anaerobic Pyrolysis.

With the increase in the awareness of the public in the environmental impact of oil shale utilization, it is of interest to reveal the mobility of potentially toxic trace elements in spent oil shale. Therefore, the Cr and As oxidation state in a representative Jordanian oil shale sample from the El-Lajjoun area were investigated upon different lab-scale furnace treatments. The anaerobic pyrolysis was performed in a retort flushed by nitrogen gas at temperatures in between 600 and 800 °C (pyrolytic oil shale, POS). The aerobic combustion was simply performed in porcelain cups heated in a muffle furnace for 4 h at temperatures in between 700 and 1000 °C (burned oil shale, BOS). The high loss-on-ignition in the BOS samples of up to 370 g kg(-1) results from both calcium carbonate and organic carbon degradation. The LOI leads to enrichment in the Cr concentrations from 480 mg kg(-1) in the original oil shale up to 675 mg kg(-1) in the ≥ 850 °C BOS samples. Arsenic concentrations were not much elevated beyond that in the average shale standard (13 mg kg(-1)). Synchrotron-based X-ray absorption near-edge structure (XANES) analysis revealed that within the original oil shale the oxidation states of Cr and As were lower than after its aerobic combustion. Cr(VI) increased from 0% in the untreated or pyrolyzed oil shale up to 60% in the BOS ash combusted at 850 °C, while As(V) increased from 64% in the original oil shale up to 100% in the BOS ash at 700 °C. No Cr was released from original oil shale and POS products by the European compliance leaching test CEN/TC 292 EN 12457-1 (1:2 solid/water ratio, 24 h shaking), whereas leachates from BOS samples showed Cr release in the order of one mmol L(-1). The leachable Cr content is dominated by chromate as revealed by catalytic adsorptive stripping voltammetry (CAdSV) which could cause harmful contamination of surface and groundwater in the semiarid environment of Jordan.

Discovery of riociguat (BAY 63-2521): a potent, oral stimulator of soluble guanylate cyclase for the treatment of pulmonary hypertension.

Soluble guanylate cyclase (sGC) is a key signal-transduction enzyme activated by nitric oxide (NO). Impairments of the NO-sGC signaling pathway have been implicated in the pathogenesis of cardiovascular and other diseases. Direct stimulation of sGC represents a promising therapeutic strategy particularly for the treatment of pulmonary hypertension (PH), a disabling disease associated with a poor prognosis. Previous sGC stimulators such as the pyrazolopyridines BAY 41-2272 and BAY 41-8543 demonstrated beneficial effects in experimental models of PH, but were associated with unfavorable drug metabolism and pharmacokinetic (DMPK) properties. Herein we disclose an extended SAR exploration of this compound class to address these issues. Our efforts led to the identification of the potent sGC stimulator riociguat, which exhibits an improved DMPK profile and exerts strong effects on pulmonary hemodynamics and exercise capacity in patients with PH. Riociguat is currently being investigated in phase III clinical trials for the oral treatment of PH.