Dasabuvir is mainly metabolized by cytochrome P450 (CYP) 2C8 and is predominantly used in a regimen containing ritonavir. Ritonavir and clopidogrel are inhibitors of CYP3A4 and CYP2C8, respectively. In a randomized, crossover study in 12 healthy subjects, we examined the impact of clinical doses of ritonavir (for 5 days), clopidogrel (for 3 days), and their combination on dasabuvir pharmacokinetics, and the effect of ritonavir on clopidogrel. Clopidogrel, but not ritonavir, increased the geometric mean AUC of dasabuvir 4.7-fold; range 2.0-10.1-fold (P = 8·10 ), compared with placebo. Clopidogrel and ritonavir combination increased dasabuvir AUC 3.9-fold; range 2.1-7.9-fold (P = 2·10 ), compared with ritonavir alone. Ritonavir decreased the AUC of clopidogrel active metabolite by 51% (P = 0.0001), and average platelet inhibition from 51% without ritonavir to 31% with ritonavir (P = 0.0007). In conclusion, clopidogrel markedly elevates dasabuvir concentrations, and patients receiving ritonavir are at risk for diminished clopidogrel response.

Abstract:We studied the incidence of fatal adverse drug reactions (ADRs) in a tertiary hospital to find out which drugs were involved. The secondary objective was to compare the data from the same hospital published 12 years earlier. All 1708 death cases in the Helsinki University Central Hospital during the year 2012 were retrospectively evaluated. All suspected drug-related deaths, excluding suicides, were scrutinized by an expert panel using the WHO ADR probability classification. Of all cases, 52 (3.0%) were classified as certainly or probably drug related and 24 (1.4%) as possibly drug related. Together, these corresponded to 0.02% of all hospital admissions. The most commonly involved drugs in certain or probable cases were cytostatics (18 cases, 1.1% of all cases) and antithrombotics (17, 1.0%). Twelve years earlier, these caused 27 (1.8%) and 22 (1.5%) cases, respectively. Non-steroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids caused less (2 and 0 cases) fatal ADRs than earlier (12 and 4 cases, p = 0.048 and p = 0.005, respectively). Most of the ADRs leading to death were present already in admission and affected seriously ill or elderly patients. Hospital-born fatal ADRs occurred in 0.003% of patients. In conclusion, cytostatics and antithrombotics are still the leading causes of fatal ADRs, but NSAIDs and glucocorticoids seem to cause fatal ADRs less often than previously. The incidence of fatal ADRs in 2012 was 3.0% of all deaths, suggesting a decline compared to the 2000 value (5.0%). Improved awareness, prevention and treatment of ADRs and safer medicines may explain these declining trends.

Xanthine oxidase inhibitors febuxostat and allopurinol are commonly used in the treatment of gout. Febuxostat inhibits the breast cancer resistance protein (BCRP) in vitro. Rosuvastatin is a BCRP substrate and genetic variability in BCRP markedly affects rosuvastatin pharmacokinetics. In this study, we investigated possible effects of febuxostat and allopurinol on rosuvastatin pharmacokinetics. In a randomized crossover study with 3 phases, 10 healthy volunteers ingested once daily placebo for 7 days, 300 mg allopurinol for 7 days, or placebo for 3 days, followed by 120 mg febuxostat for 4 days, and a single 10 mg dose of rosuvastatin on day 6. Febuxostat increased the peak plasma concentration and area under the plasma concentration-time curve of rosuvastatin 2.1-fold (90% confidence interval 1.8-2.6; P = 5 × 10 −5) and 1.9-fold (1.5-2.5; P = 0.001), but had no effect on rosuvastatin half-life or renal clearance. Allopurinol, on the other hand, did not affect rosuvastatin pharmacokinetics. In vitro, febuxostat inhibited the ATP-dependent uptake of rosuvastatin into BCRP-overexpressing membrane vesicles with a half-maximal inhibitory concentration of 0.35 µM, whereas allopurinol showed no inhibition with concentrations up to 200 µM. Taken together, the results suggest that febuxostat increases rosuvastatin exposure by inhibiting its BCRP-mediated efflux in the small intestine. Febuxostat may, therefore, serve as a useful index inhibitor of BCRP in drug-drug interaction studies in humans. Moreover, concomitant use of febuxostat may increase the exposure to BCRP substrate drugs and, thus, the risk of dose-dependent adverse effects. Gout is an increasingly common condition, and the most common form of inflammatory arthritis in developed countries. The main cause of gout is chronic hyperuricemia. Elevated serum uric acid concentration leads to accumulation of monosodium urate in joints, where urate crystals cause an extremely painful inflammatory arthritis and recurrent gout flares. Risk factors for gout include obesity, renal failure, genetic variability, diet, medications, such as diuretics, and excessive consumption of alcohol. 1-4 The increasing prevalence rates of gout worldwide are concordant with the role of lifestyle in its development. Allopurinol is the first-line treatment of chronic hyperuricemia and gout. It is used as a long-term medication to prevent attacks of gout and avoid permanent damage to the joints. Being a nonselective inhibitor of the xanthine oxidase enzyme, allopurinol prevents biotransformation of