Road Map to the ITC Transporter White Paper For Drug Development

Transcription

1 Road Map to the ITC Transporter White Paper For Drug Development Highlights of: Membrane Transporters in Drug Development, Kathleen Giacomini (UCSF), Shiew-Mei Huang (FDA), Donald J. Tweedie (Boehringer Ingelheim), Leslie Benet (UCSF) et al. (the full list of authors may be found on p. 216 in Box 1), Nature Reviews Drug Discovery, Volume 9, March 2010, pp March 2010 Copyright 2010

2 Road Map to the ITC Transporter White Paper For Drug Development Numerous studies have suggested that transporters play a part in vivo in drug disposition, therapeutic efficacy and adverse drug reactions. (p. 215) The Transporter White Paper published in the March 2010 issue of Nature Reviews - Drug Discovery is the result of work by the International Transporter Consortium. The Consortium was formed in 2007 by Kathleen Giacomini (UCSF), Donald Tweedie (Boehringer-Ingelheim), Toshi Ishikawa (RIKEN Yokohama Institute) and Shiew-Mei Huang (US FDA) and consists of key opinion leaders from the FDA, pharmaceutical industry and academia. The Consortium was formed to discuss methodologies and to propose recommendations for transporter studies to guide drug development. The ITC met periodically from and participated in the FDA-DIA Critical Path Transporter Workshop in October The White Paper was written to provide guidance for the use of preclinical and clinical transporter drug drug interaction (DDI) studies to support drug development and labeling. On March 17, 2010 the FDA Advisory Committee for Pharmaceutical Science and Clinical Pharmacology recommended that new drugs be routinely assessed for DDIs mediated by the seven transporters in the White Paper. A summary of key passages in the Transporter White Paper follows. Location in White Paper (Page #) For Use with draft Drug Interaction Guidance The White Paper is to be used in conjunction with the draft FDA Guidance: Drug Interaction Studies Study Design, Data Analysis, and Implications for Dosing and Labeling which provides specific in vitro and in vivo studies for metabolizing enzymes such as CYPs, but is lacking in details for transporters. 215, Support Drug Development The purpose of the White Paper is to provide guidance for preclinical and clinical transporter studies to support the development and regulatory submission of new drugs. 215, Ensure Safety The main goals are to ensure drug safety during clinical development and to provide adequate labeling language for marketed products. 215, 229, Known Transporter Mediated DDIs Known transporter mediated drug interactions are presented in Table 3. Affected drugs include: statins (pravastatin, rosuvastatin, pitavastatin), glyburide, bosentan, cidofovir, furosemide, acyclovir, metformin, pindolol, varenicline, pilsicainide, dofetilide, digoxin, and topotecan. Drugs causing transporter mediated DDIs include: cyclosporine, rifampicin, lopinavir, ritonavir, probenecid, cimetidine, cetirizine, quinidine, dronedarone, ranolazine and GF Transporter DDI information is becoming common on currently approved drug labels. 229 the FDA has recently asked for post-marketing studies of potential transporter mediated drug drug interactions more than a quarter of the clinical pharmacology PMC and PMR reports were related to drug-drug interactions. Of these, many of the more recent requests were related to evaluation of potential transporter-based drug-drug interactions. Shiew-Mei Huang (CDER, FDA), Janet Woodcock (CDER, FDA), NRDD, March 2010, Volume 9, p Copyright 2010 Page 2 of 6

3 Location in White Paper (Page #) Scope: Seven Transporters Study Timing The focus of the Transporter White Paper is on seven transporters (P-gp, BCRP, OCT2, OAT1, OAT3, OATP1B1 and OATP1B3), which were chosen because they have demonstrated clinical relevance for drug disposition and safety. Studies should be done at appropriate times to support clinical trials and FDA submissions. As with CYPs, preclinical transporter work should be completed in time to guide clinical DDI studies. Clinical DDI studies should be completed as needed during development to guide clinical trial design for exclusion/inclusion criteria and safety monitoring. This information will also be used for dosage and labeling information for approved drugs. 216, 220, 221, 224, 226, 228, Study Decision Trees Study decision trees are presented for the seven transporters with the ultimate goal being the determination of whether a clinical DDI study is warranted or not. Each transporter has two decision trees one to assess whether the drug or NCE is a substrate and another tree to assess whether it is an inhibitor. "The decision trees that were constructed included conservative criteria for each decision so as to reduce false negatives." 221, 224, 226, 228, 232 P-gp, BCRP P-gp and BCRP substrate assessments are presented in Box 2. P-gp and BCRP inhibition assessments are presented in Box OCT2, OAT1, OAT3 OCT2, OAT1 and OAT3 substrate assessments are presented in Box 4. OCT2, OAT1 and OAT3 inhibition assessments are presented in Box OATP1B1, OATP1B3 OATP1B1 and OATP1B3 substrate assessments are presented in Box 6, a. OATP1B1 and OATP1B3 inhibition assessments are presented in Box 6, b. Inhibition Assessment: DDI Perpetrators Drugs or NCEs that inhibit a given transporter may be a DDI perpetrator. Perpetrators can cause other drugs to become unsafe if they inhibit a transporter that is key to controlling the disposition of the victim drug. 217 Substrate Assessment: DDI Victims Drugs that are transporter substrates may become a DDI victim. Victim drugs can become unsafe in the presence of inhibitors if they rely on the transporter to limit absorption or to significantly facilitate elimination. 217 Copyright 2010 Page 3 of 6

4 Location in White Paper (Page #) BCS Class and Elimination Route Considerations for Substrates Factors such as chemical structure, routes of elimination and physicochemical properties including solubility and permeability can be taken into account to determine whether a substrate assessment is necessary for a given transporter. Even if a given transporter is inhibited, a drug may not become a DDI victim if it has high permeability or is eliminated in a different organ. "For example, an NME that is cleared exclusively by the kidneys should not (initially) be evaluated as a substrate for the hepatic transporter OATP1B1." However, structure based assumptions should be used with caution. For example, OAT3 substrates are typically negatively charged while the positively charged cimetidine is a transported substrate of OAT3. 221, 226, 223 Inhibitors of Any BCS Class or Elimination Route Can Cause a DDI Criteria such as BCS classification or routes of elimination are not presented in the White Paper for excluding inhibition assessment of an NCE or drug. The solubility, permeability or elimination route of an inhibitor does not prevent it from making a victim drug unsafe. Additionally, the structures and physicochemical properties of inhibitors can vary widely because inhibition can be caused both by substrates (competitive inhibition) and by nonsubstrates. For instance, OCT2 substrates tend to be hydrophilic while non-transported inhibitors may be highly hydrophobic , 223 Preclinical Study Design Considerations Many preclinical models are available to study drug-transporter interactions, including polarized cells, non-polarized cells, membranes and sandwich cultured hepatocytes Model Appropriate to Development Stage A model should be chosen that is appropriate for the stage of the compound. One that is useful during drug discovery may have drawbacks that make it less suitable for development when more definitive results are desired. For example, in silico models depend on a relevant training set and such models tend to predict inhibition activity better than they predict substrate transport. Membrane-based in vitro systems such as insect vesicles are convenient but suffer from high rates of false positives and false negatives and may be problematic with hydrophobic compounds , Clinical Trial Inhibitor and Substrate Choice Other Considerations Known probe substrates and inhibitors are listed in Tables 1 & 2 and are discussed in the respective decision trees. Considerations for which probes to use should include whether the drug is likely to be co-administered in the target patient population. As new information is gleaned, decision trees may evolve and may be forthcoming for additional transporters. Additionally, elucidating the role of transporters in drug disposition can be complicated by factors such as competing transporters, interplay with metabolizing enzymes, the lack of selective substrates and inhibitors for some transporters and the lack of antibodies to quantify transporter protein levels. However, this should not be seen as a reason not to move forward with a clinical (or preclinical) drug interaction study, as the primary reason for conducting a drug interaction study is to provide information for dose adjustments. 218, 219, 221, 224, 226, 228, 228-9, 232 Copyright 2010 Page 4 of 6

5 Experimental Strategy For Transporter DDI Assessment of Development Compounds The Transporter White Paper published in the March 2010 issue of Nature Reviews - Drug Discovery provides decision trees for substrate and inhibition assessment of seven clinically relevant transporters. The White Paper affords flexibility in the implementation of substrate and inhibition studies. An experimental strategy that is consistent with the recommendations outlined in the White Paper is illustrated below. The strategy is intended to achieve the stated goals of ensuring patient safety during clinical trials and to provide dosing information for approved drug labels. This strategy illustrated below was constructed in the spirit of the White Paper where each decision tree was conservatively designed to reduce false negatives (p. 232), yet not to burden sponsors with extraneous, expensive or difficult studies. NCE / Drug is Identified for Development Inhibition Considerations Substrate Considerations Inhibitors can be substrates or non-substrates (p. 219). Inhibitors can have rather different structures than substrates (pp. 219, 223). Regardless of the physicochemical properties and routes of elimination of an inhibitor, if it is present it can make a victim (substrate) drug unsafe. Affordable in vitro inhibition assays are readily available in relevant in models for all seven transporters. Inhibition Evaluation Perform in vitro screen of NCE / drug for inhibition of each of the 7 transporters regardless of structure, physicochemical properties or routes of elimination If strong inhibition of a given transporter is observed during screening, follow the appropriate White Paper decision tree Substrate Evaluation Consider structure, physicochemical properties and routes of elimination to determine whether or not an in vitro substrate screen is warranted for a given transporter If strong substrate activity is seen with a given transporter during screening, follow the appropriate White Paper decision tree Transporters can be specific to a class of compounds. For example, OCTs transport compounds with a positive charge. OATs transport compounds with a negative charge, though can also transport positively charged compounds such as cimetidine (p.223). Transported compounds with low metabolism, limited routes of elimination, low permeability or low solubility are more prone to falling victim to transporter mediated drug interactions (p. 221). Copyright 2010 Page 5 of 6

6 We welcome your feedback and comments. Contact us at: David A. Lustig, Ph.D. Inc. 115 Constitution Drive #7 Menlo Park, CA 94025, USA Tel: Toll free: 888-OPTIVIA ( ) Web: About Optivia, Inc. is an in vitro transporter assay service provider located in the San Francisco Bay Area in Menlo Park, CA. The Optivia team includes industry veterans with extensive experience in transporters, DMPK/ADME, drug discovery and drug development. Our extended team includes UCSF Professor Les Benet who sits on our Scientific Advisory Board. Optivia's proprietary technology allows the creation of transporter assays that more closely model human biology. Only Optivia provides all assays in polarized mammalian cells while other companies use frog or insect based models or non-polarized models. Optivia provides polarized mammalian cell assays for transport and inhibition studies for all seven FDA transporters. Optivia customers and collaborators include major pharmaceutical and biotechnology companies, leading academic groups and research institutions. Copyright 2010 Page 6 of 6