Posaconazole-ibrutinib interaction cannot be avoided by staggered dosing: How to optimize ibrutinib dose during posaconazole treatment.

AIMS: Ibrutinib is used in the treatment of certain B-cell malignancies. Due to its CYP3A4-mediated metabolism and highly variable pharmacokinetics, it is prone to potentially harmful drug-drug interactions. METHODS: In a randomized, placebo-controlled, three-phase crossover study, we examined the effect of the CYP3A4-inhibiting antifungal posaconazole on ibrutinib pharmacokinetics. Eleven healthy participants ingested repeated doses of 300 mg of posaconazole either in the morning or in the evening, or placebo. A single dose of ibrutinib (30, 70 or 140 mg, respectively) was administered at 9 AM, 1 or 12 h after the preceding posaconazole/placebo dose. RESULTS: On average, morning posaconazole increased the dose-adjusted geometric mean area under the plasma concentration-time curve from zero to infinity (AUC0-∞ ) and peak plasma concentration (Cmax ) of ibrutinib 9.5-fold (90% confidence interval [CI] 6.3-14.3, P < 0.001) and 8.5-fold (90% CI 5.7-12.8, P < 0.001), respectively, while evening posaconazole increased those 10.3-fold (90% CI 6.7-16.0, P < 0.001) and 8.2-fold (90% CI 5.2-13.2, P < 0.001), respectively. Posaconazole had no significant effect on the half-life of ibrutinib, but substantially reduced the metabolite PCI-45227 to ibrutinib AUC0-∞ ratio. There were no significant differences in ibrutinib pharmacokinetics between morning and evening posaconazole phases. CONCLUSIONS: Posaconazole increases ibrutinib exposure substantially, by about 10-fold. This interaction cannot be avoided by dosing the drugs 12 h apart. In general, a 70-mg daily dose of ibrutinib should not be exceeded during posaconazole treatment to avoid potentially toxic systemic ibrutinib concentrations.

Frailty and Co-Prescribing of Potentially Interacting Drugs in New Users of Warfarin.

BACKGROUND: Warfarin is underutilised in frail older people because of the fear of bleeding complications. Drug interactions are an independent bleeding risk factor. However, the extent to which potential drug interactions are taken into account at warfarin therapy initiation in frail patients is not known. OBJECTIVE: The objective of this study was to investigate the use of potentially interacting drugs increasing the bleeding risk before and after warfarin initiation in frail and non-frail patients. METHODS: We conducted an observational study including inpatients aged ≥ 60 years initiated on warfarin in a tertiary hospital in Adelaide, South Australia. Frailty status was assessed with the Reported Edmonton Frail Scale. Medication charts were reviewed before and after warfarin initiation. RESULTS: In total, 151 patients (102 non-frail and 49 frail) were included. Before warfarin initiation, the use of clopidogrel and acetaminophen was more common in frail patients compared with non-frail patients (25.5% vs 10.2%, p = 0.0135, 63.8% vs 35.7% p = 0.0014, respectively). The use of non-steroidal anti-inflammatory drugs, 9.2% in non-frail patients and 6.4% in frail patients before warfarin initiation, was completely stopped after warfarin initiation in both groups. The use of antiplatelet drugs decreased from 56.1% in non-frail patients and 66.0 % in frail patients to 12.2% and 14.9%, respectively. Instead, the use of drugs affecting the metabolism of warfarin or vitamin K increased in both groups. No statistically significant difference was seen in the exposure to interacting drugs between study groups after warfarin initiation. Acetaminophen, senna glycosides and cytochrome P450 2C9 inhibiting drugs were the most common interacting drugs at discharge used in 49.0%, 18.4% and 20.4% of non-frail patients and 53.2%, 29.8% and 19.1% of frail patients, respectively. CONCLUSIONS: The overall frequency of potential drug interactions was moderate and frail patients were not exposed to warfarin drug interactions more often than non-frail patients. Further studies in larger study populations are required to verify these results.

Statins do not Increase the Rate of Bleeding Among Warfarin Users.

Clinical significance of potential interaction between warfarin and statins is unclear. Our objective was to determine whether use of statins as a class or use of simvastatin modulates the rate of bleeding requiring hospitalization among new warfarin users. Using Finnish healthcare databases, we identified a cohort of 101,588 warfarin initiators between 1 January 2009 and 30 June 2012. By the end of 2012, these patients accumulated 92,695 person-years of exposure to warfarin-only and 60,253 years of exposure to warfarin-with-statin. The outcome was a composite of gastrointestinal, intracranial or other bleeding leading to hospitalization. A Poisson generalized estimating equation model was employed to estimate rate ratios (RR) and their 95% confidence intervals (CI) for exposure to warfarin-with-statin compared to warfarin-only and to allow multiple episodes per patient and time-dependent covariates. In multivariable models, we found no difference in the bleeding rate in association with exposure to any statin (multivariable-adjusted RR = 0.98, 95% CI 0.89-1.07) or to simvastatin (RR = 1.01, 95% CI 0.91-1.11) with warfarin compared to exposure to warfarin-only. We conclude that concomitant use of statins and warfarin was not associated with an increased rate of bleeding requiring hospitalization.

Influence of stroke and bleeding risk on prescribing of oral anticoagulants in older inpatients; has the availability of direct oral anticoagulants changed prescribing?

BACKGROUND: Little is known about changes in prescribing practices in Australia since the introduction of the direct oral anticoagulants (DOACs). Our objective was to examine if the availability of DOACs has coincided with a change in prescribing of oral anticoagulants in older hospital inpatients with regard to risk factors for stroke and bleeding. METHODS: A prospective observational study was conducted between October 2012 and August 2015 of inpatients aged over 60 years initiated on an oral anticoagulant in a large metropolitan, tertiary referral, public teaching hospital in Australia. Treatment groups were patients who commenced an oral anticoagulant prior to inclusion of DOACs on the formulary and those who commenced after the introduction of DOACs. Subgroup analyses were conducted in patients with atrial fibrillation (AF). Differences in clinical characteristics and risk for stroke and bleeding were calculated using the CHADS2 and HAS-BLED scores, respectively, were examined. RESULTS: A total of 289 patients were included. Inpatients prescribed an oral anticoagulant after the introduction of DOACs were significantly older, a greater proportion were female and more likely to have had a prior stroke. This was associated with a statistically higher CHADS2 score in the post-DOAC group. Similar findings were observed when limiting the sample to patients with AF. Patients with AF who were at greatest likelihood of having a bleeding event were less likely to be treated with a DOAC. CONCLUSION: Since the introduction of the DOACs, patients who may have previously received no therapy or suboptimal treatment were now more likely to be receiving anticoagulation, suggesting an appropriate change in prescribing practice.

Co-Prescribing of Potentially Interacting Drugs during Warfarin Therapy - A Population-Based Register Study.

We analysed the occurrence of co-prescribing of potentially interacting drugs during warfarin therapy in the community-dwelling population of Finland. We identified drugs having interaction potential with warfarin using the Swedish Finnish INteraction X-referencing drug-drug interaction database (SFINX) and obtained data on drug purchases from the nationwide Prescription Register. We defined warfarin users as persons purchasing warfarin in 2010 (n = 148,536) and followed them from their first prescription in 2010 until the end of the calendar year. Co-prescribing was defined as at least 1-day overlap between warfarin and interacting drug episodes. In addition, we identified persons who initiated warfarin therapy between 1 January 2007 and 30 September 2010 (n = 110,299) and followed these incident users for a 3-month period since warfarin initiation. Overall, 74.4% of warfarin users were co-prescribed interacting drugs. Co-prescribing covered 46.4% of the total person-years of warfarin exposure. Interacting drugs that should be avoided with warfarin were co-prescribed for 13.4% of warfarin users. The majority of the co-prescriptions were for drugs that are not contraindicated during warfarin therapy but require special consideration. Among incident users, 57.1% purchased potentially interacting drugs during the 3-month period after initiation, while 9.0% purchased interacting drugs that should be avoided with warfarin. To conclude, the occurrence of co-prescribing of potentially interacting drugs was high during warfarin therapy. Our findings highlight the importance of close monitoring of warfarin therapy and the need for further studies on the clinical consequences of co-prescribing of interacting drugs with warfarin.

The effect of drug interactions on bleeding risk associated with warfarin therapy in hospitalized patients.

BACKGROUND: Bleeding is a serious adverse drug reaction associated with warfarin therapy, often induced by interacting co-medication. METHODS: We investigated the frequency and clinical consequences of warfarin drug interactions utilizing medical records of 6,772 warfarin-treated in-patients of Turku University Hospital. RESULTS: A total of 48% of warfarin-treated in-patients were exposed to interacting co-medication. Adjusted odds ratio (OR) for bleeding was highest for cytochrome P450 2C9 (CYP2C9) inhibitors (OR 3.6; 95% confidence interval (CI) 2.4-5.6). Non-selective non-steroidal anti-inflammatory drugs (NSAID) and coxibs were associated with a bleeding risk of a similar magnitude (OR 2.6; 95% CI 1.6-4.2 and OR 3.1; 95% CI 1.4-6.7, respectively). Selective serotonin re-uptake inhibitors (SSRI) were associated with a remarkably higher bleeding risk than non-SSRIs (OR 2.6; 95% CI 1.5-4.3 and OR 1.2; 95% CI 0.3-4.3, respectively). Odds ratio for bleeding in the platelet aggregation inhibitor group was 1.6 (95% CI 0.8-3.1). CONCLUSION: We conclude that co-medication in warfarin-treated in-patients is common and should be carefully evaluated to decrease the bleeding risk associated with warfarin therapy.