Guide to drug porphyrogenicity prediction and drug prescription in the acute porphyrias

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Abstract
What is already known about this subject• Many drug safety lists for acute porphyrias, largely based on anecdotal evidence, are put forward, but no methods or rationale for the risk estimates are given.• Many unexplained discrepancies between the lists exist.What this study adds• A standardized method for assessment of the risk that a certain drug may activate these diseases has been developed.• It also allows risk assessments for drugs lacking porphyria related clinical experience.• About one thousand therapeutic drugs have been classified with regard to porphyrogenicity by the proposed method, which is most valuable for the care of porphyria patients.Aims: This paper addresses two common problems in the care of carriers of acute porphyria: the choice of safe drugs for pharmacotherapy and the strategy to apply when potentially unsafe drugs cannot be avoided.Methods and results: A technique is presented for prediction of risk that a certain drug may activate the disease in a gene carrier for acute porphyria. It is based on a model explaining the clinical manifestations as a result of the acute overloading of a deficient enzyme within the hepatic heme biosynthetic chain. The capacity of the drug for induction of the rate‐limiting enzyme in heme biosynthesis, e.g. housekeeping 5‐aminolevulinate synthase (ALAS1), is assessed by critical appraisal of reports of the outcomes of clinical use of the drug, and by theoretical criteria. The assessment occurs within the frame of a flow‐scheme employing variables of increasing specificity, i.e. endocrine properties of the drug, structure and metabolism pointing to affinity to cytochrome P450, hepatic load in therapeutic use, recognized affinity to major CYP species, capacity for CYP‐induction or irreversible inhibition, and capacity to activate or modulate the transduction mechanisms of nuclear receptors affecting ALAS1‐gene transcription. It is proposed that in the absence of a safer alternative, an urgently needed drug not should be withheld on the grounds of potential porphyrogenicity. After risk‐benefit analysis it should be prescribed, but individualized preventive measures adapted to patient vulnerability may be needed.Conclusions: About 1000 therapeutic drugs categorized with regard to porphyrogenicity by the technique proposed are presented on the internet (http://www.drugs‐porphyria.org).