Pharmacokinetic Variability of Drugs Used for Prophylactic Treatment of Migraine

Abstract

In this review, we evaluate the variability in the pharmacokinetics of 11 drugs with established prophylactic effects in migraine to facilitate 'personalized medicine' with these drugs. PubMed was searched for 'single-dose' and 'steady-state' pharmacokinetic studies of these 11 drugs. The maximum plasma concentration was reported in 248 single-dose and 115 steady-state pharmacokinetic studies, and the area under the plasma concentration-time curve was reported in 299 single-dose studies and 112 steady-state pharmacokinetic studies. For each study, the coefficient of variation was calculated for maximum plasma concentration and area under the plasma concentration-time curve, and we divided the drug variability into two categories; high variability, coefficient of variation >40%, or low or moderate variability, coefficient of variation <40%. Based on the area under the plasma concentration-time curve in steady-state studies, the following drugs have high pharmacokinetic variability: propranolol in 92% (33/36), metoprolol in 85% (33/39), and amitriptyline in 60% (3/5) of studies. The following drugs have low or moderate variability: atenolol in 100% (2/2), valproate in 100% (15/15), topiramate in 88% (7/8), and naproxen and candesartan in 100% (2/2) of studies. For drugs with low or moderate pharmacokinetic variability, treatment can start without initial titration of doses, whereas titration is used to possibly enhance tolerability of topiramate and amitriptyline. The very high pharmacokinetic variability of metoprolol and propranolol can result in very high plasma concentrations in a small minority of patients, and those drugs should therefore be titrated up from a low initial dose, depending mainly on the occurrence of adverse events.

Pharmacokinetics and Pharmacological Properties of Chloroquine and Hydroxychloroquine in the Context of COVID‐19 Infection

“…In addition, hydroxychloroquine is considered a weak inhibitor of CYP2D6, and 400 mg daily hydroxychloroquine dose increased metoprolol by 50.7%. 54,55 Table 4 presents results of clinical drug interaction studies involving hydroxychloroquine as the precipitant and the object, respectively.…”

“…concluded coadministration of hydroxychloroquine with methotrexate causes reduced C max while delaying T max and lack of any significant drug interactions related to effects on the PK of hydroxychloroquine by methotrexate. In addition, hydroxychloroquine is considered a weak inhibitor of CYP2D6, and 400 mg daily hydroxychloroquine dose increased metoprolol by 50.7% 54,55 . Table 4 presents results of clinical drug interaction studies involving hydroxychloroquine as the precipitant and the object, respectively.…”

Efficacy and safety of erenumab (AMG334) in episodic migraine patients with prior preventive treatment failure: A subgroup analysis of a randomized, double-blind, placebo-controlled study

“…Commonly used preventive medications, such as topiramate, propranolol, and amitriptyline, have been repurposed from other indications rather than designed to target a specific pathophysiological mechanism in migraine (5). These treatments are often limited by insufficient efficacy and poor tolerability (6,7), and may require dose titration during initiation in an attempt to mitigate the impact of adverse effects, which can delay the onset of efficacy (7). As a consequence of these limitations, currently used preventive medications are associated with high failure rates and low adherence (8).…”

The effect of gender differences on the use of valproic acid for migraine prophylaxis

“…Variability of the dose-response mainly depends on three factors: 1-factors associated with the disease mechanism, which are unknown for prophylactic migraine drugs; 2-pharmacodynamics, also unknown for such drugs; 3-pharmacokinetic factors. Metoprolol, propranolol, and amitriptyline have high pharmacokinetic variability, whereas valproate, topiramate, atenolol, naproxen, and candesartan have low pharmacokinetic variability; however, factors determining this variability are poorly understood (14). Another study shows that age and gender significantly influence valproate serum concentrations but several publications have reported no effects of age on total valproate serum concentrations (15,16).…”