Vortioxetine pharmacokinetics, writ small and large


This review of the pharmacokinetics of vortioxetine (G. Chen and colleagues, Clinical Pharmacokinetics 57:6:673-686, 2018), approved for treatment of depression and withal alleged to enhance cognition by increasing alertness, reminds us of how useful clinically can be knowing how long it takes for peak blood concentrations to fall by half (elimination half-life), how long is required for drug blood concentrations to reach steady state (when the amount of drug entering the arterial circulation equals the amount cleared over the same duration), and which drugs to avoid coadministering by virtue of how much they may increase or reduce its hepatic metabolism.

Having reviewed the preclinical findings that informed its prescribing in clinical trials, the authors found that vortioxetine confers antidepressant effects that are safe and tolerable at daily dosages of five to 20 milligrams (of which 75 percent reaches the arterial circulation), and is absorbed orally to similar extents in fed and fasted states. It has an elimination half-life of 66 hours, and its steady-state blood concentrations at a given dose occur on average at two weeks after a first dose (consistent with the rule of thumb that steady-state is reached in five half-lives). The clearance of vortioxetine, they found, occurs by dint of metabolism by hepatic CYP2D6 (to a major metabolite that lacks clinical activity and a minor metabolite to which the blood-brain barrier is impermeable ) and hepatic conjugation with glucuronic acid (via uridinyl glucuronosyltransferase) to increase its aqueous solubility during renal clearance.

Besides similar bioavailabililty after oral dosing in fed and fasted states, vortioxetine’s bioavailability is unrelated to age, sex, body mass index, and differences in hepatic or renal functional activity within the normal range. Persons with low-activity allelic variants of CYP2D6 (so-called poor metabolizers) develop higher blood concentrations of vortioxetine at equivalent dosages, and the increment may be clinically significant, relative to blood concentrations in persons with “wild-type” (normal-activity) alleles of CYP2D6. So, too, according to the authors’ review, may be decrements of vortioxetine blood concentrations during coadministration of “universal inducers,” such as phenytoin, carbamazepine, and rifampicin, which do not induce CYP2D6, but withal have been reported to reduce blood concentrations of other CYP2D6 substrates and substrates of other cytochrome isoenzymes. That “rescue pathways” of metabolism do not contribute to hepatic metabolism of vortioxetine comports with absence among the studies the authors reviewed of increased blood concentrations of vortioxetine when coadministered or incubated in vitro with inhibitors of cytochrome isoenzymes other than CYP2D6 or of reduced blood concentrations during coadministration with specific inducers of CYPs 1A2, 3A4, 2C9, 2C19, and 2B6.

(Obiter: Conclusions of pharmacokinetic studies are typically tantamount to their findings. Interpretations of the latter withal may be useful, given variable formal training in clinical pharmacology among psychiatric residency training programs and those intended to qualify non-M.D. prescribers. Accordingly, vortioxetine’s long (66-hour) elimination half-life does not necessarily indicate a duration of action or a latency preceding withdrawal symptoms (yet to be characterized) longer than those of drugs with more rapid clearance. Vortioxetine and other psychotropic drugs act in the brain and clearance studies calculate clearance rates from concentrations in blood: Proportionality of drug distribution and tissue compartmental retention (more closely correlated with clinical activity than are blood concentrations, which is why durations of anxiolytic effects of long half-life diazepam and short half-life lorazepam (and acute analgesic effects of methadone and morphine) are similar. When very high or very low, volume of distribution (calculated as the volume of water required to prepare an aqueous solution of drug equal to that measured in blood) may reflect tissue distribution in vivo, and, indirectly, milligram-potency or duration of action. Vortioxetine’s is neither, and knowing its volume of distribution offers little clinical value, relative to those of other drugs of its class.

Elimination half-life is more useful in calculating time to reach steady-state blood concentrations (about five times the elimination half-life), which for vortioxetine is thirteen to fourteen days (albeit less long when drug clearance is more rapid (because of an allelic variant of CYP2D6, a duplication of the normal, wild-type allele, associated with “ultra rapid” metabolism, and longer when it is slower, as in “poor metabolizers” who have inherited a CYP2D6 allelic variant that transcribes to a slowly metabolizing CYP2D6 enzyme). Similarly affected are times to reach steady-state blood concentrations during coadministration of ACTH, reported to increase metabolic activity of CYP2D6, or potent inhibitors of the latter, such as bupropion, which reduce it..

Time to reach steady-state blood concentrations (determined empirically or calculated from elimination half-life) derives clinical importance by virtue of potential consequences of raising dosage before they are achieved (conducing to higher-than-expected final blood concentrations that exceed blood concentrations required for antidepressant respons,e and/or induce adverse effects absent at those lower, effective blood concentrations. Assessment of antidepressant response and tolerability and adjustment of dosage should therefore occur after steady-state blood concentrations are achieved for a given dosage. An assessment of insufficient antidepressant response before steady-state blood concentrations are achieved may precede an assessment of robust response at the same dosage at steady-state. Premature dosage increments motivated by premature assessments of insufficient response may eventuate in adverse effects that compromise response when steady-state blood concentrations of the prematurely increased dosages are reached.)

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