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

Abstract

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).

Figures

Figure 1

Flow chart for assessment of drug porphyrogenicity. In the flow-scheme, the information to use is summarized in bold letters at the heads of the seven boxes. Specific data of relevance are given within the respective boxes. The answer NO indicates that none of the statements within the box is representative for the substance, while YES indicates that one, or several of the statements are valid. Arrows point to conclusions permitted at the level in question, or to further categories of information to be considered in the evaluation. The term porphyrogenicity indicates significant potential for ALAS1-induction. 1.Clinical evidence of porphyrogenicity? A published or otherwise communicated report of clinical porphyrogenicity is taken to be well documented if it is confirmed that the patient is a gene carrier for one of the four forms of acute porphyria, if the porphyric nature of the symptoms is verified by measurements of urinary PBG concentration before as well as during the attack (or if at least the urine is examined for reddish discoloration at these times), if a causality between the administration of the drug and the clinical symptoms is made probable, and if simultaneous effects of other porphyrogenic influences are ruled out. Using these reliability criteria, three or more well documented reports will make possible direct classification of a drug as porphyrogenic, while one to two may motivate the classification probably porphyrogenic. Less well documented observations should be taken into account, e.g. where administration of the drug is only followed by reddish urine and where side-effects from other agents cannot be ruled out, or as in the case of nonrecent episodes which cannot easily be assessed by the physician. Evidently erroneous reports and observations lacking time causality being excluded, a number of five or more dependent on quality, such less well documented observations on a drug may motivate the classification probably porphyrogenic.Most carriers of acute porphyria tolerate even porphyrogenic drugs most of the time. The likelihood of failure to detect porphyrogenicity of a drug equalling (1 minus the likelihood to induce one attack in a patient cohort receiving the drug)n, n being the number of uneventful clinical observations at hand, a rather large number of observations of tolerance will therefore be needed to tell a drug with all probability free from porphyrogenic action. Allowing for intrinsic imprecision due to absence of data for the actual (but low) morbidity rate, probably more than 15 instances of uneventful use of the drug by individuals with unknown porphyric susceptibility, and at least by seven who are estimated to be susceptible (Figure 2), would be needed for a classification of the drug as probably not porphyrogenic, theoretical criteria not speaking against it (dashed arrow) and reports concerning carriers recognized to be probably unsusceptible being neglected. 2.Porphyrogenic endocrine effects? Hormones with recognized porphyrogenic effects are considered, as are hormonal effects operative within the genomic network governing the transcription of the ALAS1-gene. 3.Data on structure or pharmacology? Non-porphyrogenic drugs are ruled out by use of criteria 4–6, below. 4.Lack of CYP-affinity? Through recognition of substance categories not accessible to CYP-metabolism, drugs devoid of porphyrogenic effects are excluded from the further evaluation. 5.Probably insignificant hepatocyte exposure? By use of information on the drug regarding its dose, route of administration, steady-state plasma concentration, degree of ionization at physiological pH, protein binding, metabolism and excretion, it is estimated whether it, in therapeutic use, may give rise, or not, to hepatic exposure high enough (1 µm or higher) for initiating the nuclear receptor activation needed for ALAS1-transcription. 6.CYP-3A4 and/or 2C9 affinity? CYP affinity-data gained, e.g. via databases, reference literature, manufacturer's Summaries of Product's Characteristics (SPCs) or published reports, may show whether the drug has affinity to one or both of the two major CYPs, or not, and thus whether a potential for ALAS1-induction is a possibility (YES) or unlikely (NO). If no direct, or indirect CYP affinity-data are at hand, clinical evidence for porphyrogenicity or nonporphyrogenicity must be actively sought, e.g. via inquires, and the substance meanwhile classified as possibly porphyrogenic. 7.Capacity for ALAS1-induction? Human data pointing to activation or positive modulation of nuclear receptors mediating ALAS1-transcription, or pointing to induction of major CYP-classes, to multi-induction of enzymes or to irreversible CYP-inhibition (YES), indicate probable porphyrogenicity of the drug, with weak effects being ignored. Animal data are given less significance, but taken to motivate the classification possibly porphyrogenic. Data indicating that CYP-induction does not take place via any of the mechanisms or CYP inhibition (NO), point to the substance as probably not porphyrogenic.In the absence of data regarding the ALAS1 induction capacity of the substance (NO DATA), clinical evidence must be actively sought, e.g. via inquires directed against patients or doctors, and the substance meanwhile classified as possibly porphyrogenic

Figure 2

Preventive measures in prescription of porphyrogenic drugs to a carrier of acute porphyria. A potentially porphyrogenic drug is not to be prescribed for a carrier of acute porphyria other than on urgent indication and where safer alternatives are unavailable. In such a case, and after risk-benefit analysis, preventive measures adapted to the individual porphyric vulnerability of the patient are undertaken, including careful monitoring of the disease activity and administration of disease de-activating agents, i.e. carbohydrate or heme. Assessment of the probable vulnerability of the carrier patient to ALAS1-inducing agents is made on the basis on his or her age and sex, previous and immediate disease activity, and possible current exposure to other porphyrogenic agents. The set of preventive measures to take in the individual case depends on the degree of porphyric susceptibility of the individual and on the potential porphyrogenicity of the drug to be administered