Adverse events caused by drug interactions involving glucuronoconjugates of zidovudine, valproic acid and lamotrigine, and analysis of how such potential events are discussed in package inserts of Japan, UK and USA.

BACKGROUND AND OBJECTIVE: As pharmacokinetic drug interactions frequently cause adverse events, it is important that the relevant information is given in package inserts (PIs). We previously analysed the provision of PIs for HMG-CoA reductase inhibitors and Ca antagonists, for which metabolism by cytochrome P450 could be a major interaction mechanism. In this article, we focus on interactions involving glucuronoconjugates because many drugs and their metabolites undergo this conjugation. METHODS: We reviewed clinical drug interactions related to glucuronoconjugates, focusing on reports of adverse events. Then, we picked out three important drugs (zidovudine, valproic acid and lamotrigine), and examined how the literature information is reflected in the relevant PIs in Japan, UK and USA. RESULTS AND DISCUSSION: Pharmacokinetic interactions related to glucuronoconjugates were found with 33 drug combinations. Of these, five combinations induced clear adverse events: (i) severe anaemia due to zidovudine and caused by interaction with valproic acid, (ii) recurrence/increased frequency of seizure or increased manic states from a reduction in therapeutic effects of valproic acid caused by panipenem, (iii) meropenem or (iv) ritonavir and (v) of lamotrigine caused by oral contraceptives. Analysis of PIs showed a lack of description of the interaction of zidovudine with valproic acid in the Japanese PI. The UK PI mentioned this interaction without quantitative data, whereas full information was given in the US PI. A lack of description was also present on the interaction between valproic acid with ritonavir, reported in 2006, in the PIs of all three countries. For the interactions involving valproic acid and panipenem or meropenem, even though marked reduction of blood valproic acid level has been reported, no quantitative data were provided in any of the PIs. CONCLUSION: Five combinations were identified to cause severe adverse events because of interactions related to glucuronoconjugates. This information, including quantitative data, is not always properly provided in the relevant PIs in Japan, UK or USA. PIs should be improved to better inform healthcare providers and thereby help them and their patients.

Pediatric susceptibility to 18 industrial chemicals: a comparative analysis of newborn with young animals.

We comprehensively re-analyzed the toxicity data for 18 industrial chemicals from repeated oral exposures in newborn and young rats, which were previously published. Two new toxicity endpoints specific to this comparative analysis were identified, the first, the presumed no observed adverse effect level (pNOAEL) was estimated based on results of both main and dose-finding studies, and the second, the presumed unequivocally toxic level (pUETL) was defined as a clear toxic dose giving similar severity in both newborn and young rats. Based on the analyses of both pNOAEL and pUETL ratios between the different ages, newborn rats demonstrated greater susceptibility (at most 8-fold) to nearly two thirds of these 18 chemicals (mostly phenolic substances), and less or nearly equal sensitivity to the other chemicals. Exceptionally one chemical only showed toxicity in newborn rats. In addition, Benchmark Dose Lower Bound (BMDL) estimates were calculated as an alternative endpoint. Most BMDLs were comparable to their corresponding pNOAELs and the overall correlation coefficient was 0.904. We discussed how our results can be incorporated into chemical risk assessment approaches to protect pediatric health from direct oral exposure to chemicals.

A literature search on pharmacokinetic drug interactions of statins and analysis of how such interactions are reflected in package inserts in Japan.

BACKGROUND AND OBJECTIVES: Statins (HMG-CoA reductase inhibitors) are one of the most widely prescribed classes of drugs throughout the world, because of their excellent cholesterol-lowering effect and overall safety profile except for rare but fatal rhabdomyolysis arising either directly or indirectly by pharmacokinetic interactions with certain other drugs. As package inserts in pharmaceuticals are the primary source of information for health care providers, we carried out a literature search to examine how crucial information was provided in package inserts of five statins approved in Japan (simvastatin, atorvastatin, fluvastatin, pravastatin and pitavastatin). METHODS: A MEDLINE search from 1996 to June 2004 was carried out to identify studies on clinical pharmacokinetic drug interactions for the five statins. We mainly collected information on area under plasma concentration (AUC) following co-administration of statins with other drugs. The current package inserts used in Japan were obtained from the website of the Pharmaceutical and Medical Device Agency whereas USA package inserts were obtained from the Food and Drug Administration website. RESULTS: The majority of package inserts listed the drugs that interacted with statins with most describing the risk of rhabdomyolysis because of the possibility of increases in blood concentration. However, quantitative information such as change in AUC was provided in only a few cases. Instructions for dosage adjustment are seldom provided in the Japanese package inserts. USA package inserts list almost identical drug interactions as the Japanese package inserts, although they contain more quantitative data, especially for typical cytochrome P450 (CYP) inhibitors. CONCLUSION: All pharmacokinetic drug interactions including relevant quantitative data for potential effectors and details on mechanisms of interaction need to be given in package inserts as soon as the information becomes available, to ensure safe and proper use of the drugs concerned. Including such information in the package insert will be an extremely valuable aid for health care providers.