Nimodipine-associated standard dose reductions and neurologic outcomes after aneurysmal subarachnoid hemorrhage: the era of pharmacogenomics.

Nimodipine, an L-type cerebroselective calcium channel antagonist, is the only drug approved by the US Food and Drug Administration for the neuroprotection of patients with aneurysmal subarachnoid hemorrhage (aSAH). Four randomized, placebo-controlled trials of nimodipine demonstrated clinical improvement over placebo; however, these occurred before precision medicine with pharmacogenomics was readily available. The standard enteral dose of nimodipine recommended after aSAH is 60 mg every 4 h. However, up to 78% of patients with aSAH develop systemic arterial hypotension after taking the drug at the recommended dose, which could theoretically limit its neuroprotective role and worsen cerebral perfusion pressure and cerebral blood flow, particularly when concomitant vasospasm is present. We investigated the association between nimodipine dose changes and clinical outcomes in a consecutive series of 150 patients (mean age, 56 years; 70.7% women) with acute aSAH. We describe the pharmacogenomic relationship of nimodipine dose reduction with clinical outcomes. These results have major implications for future individualized dosing of nimodipine in the era of precision medicine.

The effect of CYP2D6 drug-drug interactions on hydrocodone effectiveness.

OBJECTIVES: The hepatic cytochrome 2D6 (CYP2D6) is a saturable enzyme responsible for metabolism of approximately 25% of known pharmaceuticals. CYP interactions can alter the efficacy of prescribed medications. Hydrocodone is largely dependent on CYP2D6 metabolism for analgesia, ondansetron is inactivated by CYP2D6, and oxycodone analgesia is largely independent of CYP2D6. The objective was to determine if CYP2D6 medication coingestion decreases the effectiveness of hydrocodone. METHODS: This was a prospective observational study conducted in an academic U.S. emergency department (ED). Subjects were included if they had self-reported pain or nausea and were excluded if they were unable to speak English, were less than 18 years of age, had liver or renal failure, or carried diagnoses of chronic pain or cyclic vomiting. Detailed drug ingestion histories for the preceding 48 hours prior to the ED visit were obtained. The patient's pain and nausea were quantified using a 100-mm visual analog scale (VAS) at baseline prior to drug administration and following doses of hydrocodone, oxycodone, or ondansetron. We used a mixed model with random subject effect to determine the interaction between CYP2D6 drug ingestion and study drug effectiveness. Odds ratios (ORs) were calculated to compare clinically significant VAS changes between CYP2D6 users and nonusers. RESULTS: A total of 250 (49.8%) of the 502 subjects enrolled had taken at least one CYP2D6 substrate, inhibitor, or inducing pharmaceutical, supplement, or illicit drug in the 48 hours prior to ED presentation. CYP2D6 drug users were one-third as likely to respond to hydrocodone (OR = 0.33, 95% confidence interval [CI] = 0.1 to 0.8) and more than three times as likely as nonusers to respond to ondansetron (OR = 3.4, 95% CI = 1.3 to 9.1). There was no significant difference in oxycodone effectiveness between CYP2D6 users and nonusers (OR = 0.53, 95% CI = 0.3 to 1.1). CONCLUSIONS: CYP2D6 drug-drug interactions appear to change effectiveness of commonly prescribed drugs in the ED. Drug-drug interaction should be considered prior to prescribing CYP2D6 drugs.