Transporters in Drug Development: 2018 ITC Recommendations for Transporters of Emerging Clinical Importance

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Transporters in Drug Development: 2018 ITC Recommendations for Transporters of Emerging Clinical Importance

Maciej J. Zamek-Gliszczynski1, Mitchell E. Taub2, Paresh P. Chothe3, Xiaoyan Chu4, Kathleen M. Giacomini5, Richard B. Kim6, Adrian S. Ray7, Sophie L. Stocker8, Jashvant D. Unadkat9, Matthias B. Wittwer10, Cindy Xia11, Sook-Wah Yee12, Lei Zhang13, Yan Zhang14 , on behalf of the International Transporter Consortium

This white paper provides updated International Transporter Consortium (ITC) recommendations on transporters that are important in drug development following the 3rd ITC workshop. New additions include prospective evaluation of organic cation transporter 1 (OCT1) and retrospective evaluation of organic anion transporting polypeptide (OATP)2B1 because of their important roles in drug absorption, disposition, and effects. For the ﬁrst time, the ITC underscores the importance of transporters involved in drug-induced vitamin deﬁciency (THTR2) and those involved in the disposition of biomarkers of organ function (OAT2 and bile acid transporters).

The third ITC transporter workshop was held with the purpose of new recommendations are summarized under each transporter along updating recommendations on transporters in drug development. A with the evidence supporting those recommendations. key goal was to discuss transporters of emerging clinical relevance, and reach consensus on whether the clinical evidence supports NEW RECOMMENDATIONS FOR TRANSPORTERS AS incorporation of these transporters into the practice of drug develop- MEDIATORS OF CLINICAL DDIS ment. The authors of this article formed a working group to reach In this section, evidence is presented for several transporters, as consensus on emerging drug transporters of clinical relevance. Previ- mediators of clinical DDIs in the liver and intestine. In particu- ously, ITC recommendations were largely focused on transporters lar, recent clinical studies support the roles of the hepatic important in mediating drug–drug interactions (DDIs) or associated transporter, OCT1, in mediating clinically important DDIs. The with liver toxicity. In this white paper, ITC recommendations possible involvement of the organic anion transporting polypep- extend beyond transporters important in DDIs to include transport- tide 2B1 (OATP2B1) in mediating both intestinal and hepatic ers that are potentially important in mediating drug-induced vita- DDIs, needs to be considered to understand observed DDIs that min deficiencies and those that are involved in the disposition of cannot be attributed to more common mechanisms (e.g., intesti- biomarkers associated with drug-induced organ toxicities. Updated nal P-gp/BCRP, hepatic OATP1B1/1B3). Brief comments on ITC recommendations on transporters in drug development are other transporters, for which clinical evidence is sparse, are summarized in the revised ITC transporter figure (Figure 1). Below, included. current affiliation: Adrian S. Ray Discovery Biology, Nimbus Therapeutics, Cambridge, Massachusetts, USA 1Quantitative Drug Disposition, GlaxoSmithKline, King of Prussia, Pennsylvania, USA; 2Drug Metabolism and Pharmacokinetics, Boehringer Ingelheim, Ridgefield, Connecticut, USA; 3Drug Metabolism and Pharmacokinetics, Vertex Pharmaceuticals, Boston, Massachusetts, USA; 4Department of Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Kenilworth, New Jersey, USA; 5Department of Bioengineering and Therapeutic Sciences, Schools of Pharmacy and Medicine, University of California, San Francisco, California, USA; 6Division of Clinical Pharmacology, Department of Medicine, Western University, London, ON, Canada; 7Clinical Research, Gilead Sciences, Foster City, California, USA; 8Department of Clinical Pharmacology & Toxicology, St Vincent’s Hospital, Sydney, NSW, Australia & St Vincent’s Clinical School, UNSW Sydney, NSW, Australia; 9Department of Pharmaceutics, University of Washington, Seattle, Washington, USA; 10Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche, Basel, Switzerland; 11Drug Metabolism and Pharmacokinetics, Takeda Pharmaceuticals International, Cambridge, Massachusetts, USA; 12Department of Bioengineering and Therapeutic Sciences, Schools of Pharmacy and Medicine, University of California, San Francisco, California, USA; 13Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, USA; 14Drug Metabolism Pharmacokinetics & Clinical Pharmacology, Incyte, Wilmington, Delaware, USA. Correspondence: Maciej J. Zamek- Gliszczynski ([email protected]) Received 26 February 2018; accepted 1 May 2018; advance online publication 8 August 2018. doi:10.1002/cpt.1112

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Figure 1 Transporters proposed for evaluation during drug development in the intestine (a), liver (b), kidney (c), and brain (d). The transporters previously recommended for evaluation by the ITC are marked with red circles; transporters previously recommended for retrospective mechanistic explanation of clinical observations are marked with yellow circles. New transporters were highlighted on the basis of broad clinical relevance to drug interactions. OCT1 (green circle) is proposed for evaluation during drug development both for transport of substrates and inhibitory potential. Retrospective study of OATP2B1 (yellow square) is warranted in limited specific instances of DDIs or disposition otherwise unexplained by more common mechanisms. THTRs are new transporters added to the figure; however, drug inhibition of this transporter is likely relevant in the context of preexisting thiamine deficiency and, therefore, should only be considered for drugs used chronically in sensitive populations or when evidence of drug-induced thiamine deficiency is observed. Symbols for the other discussed transporters (OATP1A2, OATP4C1, OAT2, ASBT (a.k.a. IBAT), OSTa/b, NTCP, MDR3) remain as dark blue circles, because evidence is lacking for specific drug development recommendations.

Organic cation transporter 1 (OCT1) For example, selective impairment of OCT1 can reduce hepatic Human OCT1 (SLC22A1) is mainly expressed in the liver, local- metformin exposure and subsequently its antihyperglycemic ized on the sinusoidal side of hepatocytes. Hepatic OCT1 was effects, with no apparent changes in systemic pharmacokinet- discussed in the 2010 ITC white paper,1 and evaluation of inhib- ics.6,7 Furthermore, nonspecific inhibition of OCTs can reduce itors of this transporter was first recommended in European the renal clearance of metformin through OCT2 inhibition, Medicines Agency’s 2010 draft DDI guideline and remains in while simultaneously reducing the hepatic uptake of the drug their final DDI guideline for understanding potential alterations (through OCT1 inhibition); thus resulting in little net change in in metformin distribution to the liver, the primary site of metfor- hepatic drug exposure and drug response despite increased sys- min pharmacology. Practical implementation of this recommen- temic exposure, as demonstrated directly in Oct1/2-knockout dation has been challenging, because systemic exposure is the mice.4 Many OCT/MATE inhibitors are nonspecific for renal major endpoint of DDI studies in drug development. Notably, and hepatic metformin transporters, and may alter metformin OCT1 is not a determinant of metformin plasma levels, because hepatic distribution and pharmacodynamics, in addition to renal this drug is eliminated almost exclusively by the kidney.2 Metfor- clearance and systemic pharmacokinetics8 (see UCSF-FDA min clinical DDI studies, to date, have been primarily triggered TransPortal http://transportal.compbio.ucsf.edu/). As such, met- by in vitro studies of investigational drugs’ interactions with the formin DDI studies may require pharmacodynamic endpoints renal transporters, OCT2, multidrug, and toxin extrusion protein (e.g., oral glucose tolerance test) to understand the true effects of 1 (MATE1), and MATE2-K, and have focused on changes in concomitant drugs on metformin pharmacodynamics3,4,6 (see systemic metformin exposure, an endpoint that could be inade- metformin clinical DDI study design commentary in this issue).9 quate to inform rational metformin dose adjustment in DDIs.3–6 OCT1 inhibitory potential is critical, in addition to inhibitory

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substrate fenoterol, a narrow therapeutic index beta2 agonist, exhibited a 2-fold elevated systemic exposure in homozygous car- riers of OCT1 null alleles, which elicited clinically concerning 1.5-fold and 3.4-fold greater increases in heart rate and blood glucose, respectively.11 Similarly, the active O-desmethyl metabolite of tramadol, which is a substrate of OCT1, exhibited a 2-fold greater exposure, resulting in enhanced opioid pharmacodynamic activity in healthy subjects, and in clinical practice, decreased drug self-administration for postoperative pain.12,13 Further, OCT1 reduced function polymorphisms were associated with greater systemic exposure (2–4-fold) and enhanced efficacy (up to 10-fold reduction in vomiting) of the serotonin receptor (5- HT3) antagonists, ondansetron and tropisetron, in over 200 patients.14 In people harboring OCT1 reduced function polymorphisms, the systemic exposure of the antimigraine medica- tion, sumatriptan, was increased 2-fold.15 OCT1 reduced function polymorphisms have been associated with the disposition and pharmacologic effects of the opioid, morphine; however, these effects are inconsistent between studies and may be con- founded by oral administration of the prodrug vs. parenteral administration of morphine directly.16 DDIs with specific and strong inhibitors may phenocopy pharmacokinetic (PK) and possible pharmacodynamic (PD) changes of these OCT1-substrate drugs associated with genetic polymorphisms, and as such, studies with genetic polymorphisms provide clinical support for OCT1 in mediating DDIs. Based on clinical evidence, evaluation of substrate and inhibition potential for OCT1 is recommended during drug development. As a hepatic uptake transporter, existing OATP substrate and inhibitor decision trees can be extended to OCT1 (Figure 2). Note that the cutoff values shown in Figure 2 are consistent with Figure 2 Proposed addition of OCT1 to hepatic OATP substrate (a) and OATP decision trees proposed in the 2017 US Food and Drug inhibitor (b) decision trees. Note the cutoff values are consistent with Administration (FDA) in vitro DDI draft guidance, and these may OATP decision trees in the 2017 FDA in vitro DDI draft guidance. Cutoff change based on future data. The conduct of in vitro studies is gen- values may change based on future data, so the emphasis is placed not erally preferred for the clinically relevant substrate-inhibitor pairs on any specific threshold, but on the concept that OCT1 be considered in a that will be studied in the clinic; therefore, choice of the substrate manner analogous to hepatic OATPs. to use in assays will depend on concomitant medications that are most relevant for the new molecular entity (NME) under study potential to OCT2/MATE, to understand whether the pharma- and, if warranted, based on decision tree analysis, would be the cologic effect of metformin may be altered during a DDI. subject of a subsequent clinical DDI study. For example, for OCT1 inhibition is important to consider for metformin dose NMEs used in cancer patients, the sponsor may wish to consider adjustments in DDI studies that are conducted for drugs that interactions with 5-HT3 receptor antagonists that appear to be modulate metformin renal elimination. However, for reasons sensitive substrates based on the pharmacogenomics studies dis- outlined above, metformin is not a sensitive pharmacokinetic cussed above. For drugs predicted to be OCT1 substrates in vivo, probe for OCT1 inhibition. As detailed below, recent clinical as noted, there are no available specific clinical inhibitors of the studies identified several OCT1-substrate drugs whose systemic transporter. In this case, the high prevalence of homozygous car- exposure is sensitive to OCT1 modulation and may be consid- riers of OCT1 null alleles (e.g., up to 9% of Caucasians) enables ered as OCT1 systemic probe substrates. Collectively, these stud- the use of pharmacogenetic studies as a substitute for a traditional ies demonstrated that OCT1 can act as the rate-determining step DDI evaluation. Alternatively, a DDI study can be conducted with in hepatic drug clearance of these drugs in a manner conceptually a nonspecific OCT1 inhibitor with careful consideration of the analogous to hepatic OATPs. effects that inhibition of other pathways may have on the victim Recent clinical evidence from pharmacogenetic studies sup- NME. ports hepatic OCT1 as a potential target for systemic DDIs with notable pharmacokinetic and pharmacodynamic consequences Organic anion transporting polypeptide 2B1 (OATP2B1) (see accompanying white paper on clinically relevant transporter OATP2B1 (SLCO2B1) exhibits broad tissue expression relative polymorphisms in this issue of CPT).10 For example, the OCT1- to OATP1B1/1B3.17 Particularly, OATP2B1 is the main

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intestinal OATP isoform18,19 and is responsible for DDIs previ- should be considered as a mechanistic explanation of DDIs or ously attributed to OATP1A2.20 Figure 1 shows OATP2B1 as drug–fruit juice interactions upon observation of apparently an intestinal apical uptake mechanism, although apical/basolateral decreased absorption of the substrate drug. localization in enterocytes remains controversial.21,22 Additionally, recent proteomic data indicate that OATP2B1 has similar expres- Organic anion transporting polypeptide 4C1 (OATP4C1) sion as OATP1B3 in the liver,23–25 suggesting that its importance Human OATP4C1 (SLCO4C1) is localized to the basolateral 38 in hepatic uptake may have been underestimated. membrane of the renal proximal tubule. Substrates of OATP2B1 has broad substrate specificity, transporting many OATP4C1 include digoxin, ouabain, and sitagliptin.39 To date, clinically used drugs, including atorvastatin and rosuvastatin.17,26 the contribution of OATP4C1 to renal elimination of drugs and Detailed analysis of the transport kinetics of OATP2B1 revealed DDIs has not been well established beyond tubular secretion of low- and high-affinity binding sites.27 These binding sites show digoxin.40 OATP4C1 has been challenging to study due to the distinct Km and Vmax values for typical probe substrates, such as inconsistent ability to attain functional expression in vitro.A estrone-3-sulfate, pravastatin, and fexofenadine; likewise, many recent OATP4C1 in vitro inhibition screening of 53 drugs only inhibitors bind preferentially to either the high- or low-affinity identified ritonavir as a clinically relevant inhibitor.41 An unex- binding site.20,27 OATP2B1 exhibits pH-dependent transport,28 pected DDI between bupropion and digoxin was reported, where which can be clinically relevant in the intestine. Therefore, in bupropion increased renal clearance of digoxin by 80%.42 Activa- addition to standard in vitro studies at neutral pH, mechanistic tion of OATP4C1-mediated digoxin tubular secretion by bupro- evaluation at acidic conditions (e.g., pH 5.5) could potentially pion and its metabolites was proposed as the mechanistic improve in vitro to in vivo extrapolation. Several polymorphisms explanation based on in vitro studies.43 Overall, the clinical signif- of OATP2B1 have been described.29 SLCO2B1*3 (c.1457C>T) icance of OATP4C1 is not well established, and, therefore, no is the most studied variant, but clinical relevance is controversial, recommendations can be made for drug development at present. even for the same substrate drug (e.g., fexofenadine17). Drugs such as the tyrosine kinase inhibitors gefitinib and erlo- Organic anion transporting polypeptide 1A2 (OATP1A2) tinib,30 and natural products, such as naringin and hesperidin in OATP1A2 (SLCO1A2) is expressed in the brain.44 Notably, fruit juice,31 are potent inhibitors of OATP2B1. However, to OATP1A2 is not expressed in enterocytes, despite initial reports date, known inhibitors are not specific to OATP2B1 and may misattributing intestinal OATP transport to OATP1A2. interact with other transporters and drug metabolizing enzymes. Although not present in hepatocytes, cholangiocytes lining the In vivo evidence in support of intestinal OATP2B1 as a media- bile ducts express OATP1A2.45 OATP1A2 transports opioid tor of DDIs comes largely from drug–fruit juice interactions. In agonists and hydrophilic antimigraine tryptans.44,46 There is no particular, the Cmax and AUC of several OATP2B1 substrates direct clinical evidence to link OATP1A2 to enhanced drug (including fexofenadine, aliskiren, and celiprolol) were decreased entry into the central nervous system (CNS), but knockout mice 1.5–2-fold by grapefruit, apple, and orange juice.17,32–34 Inhibi- lacking the murine ortholog suggest this to be the case.47 To tion of intestinal OATP2B1 can decrease systemic exposure of date, there is no clear evidence for clinical DDIs due to brain OATP2B1 substrate drugs without increasing the terminal half- OATP1A2 inhibition, and successful targeting of OATP1A2 for life. Recent studies showed that ronacaleret, an inhibitor of CNS drug delivery has yet to be demonstrated. As such, no rec- OATP2B1, decreased rosuvastain plasma exposure by 50% with- ommendations can be made for drug development. out altering its terminal half-life.35 Hepatic OATP2B1 may play an important role in drug clear- NEW RECOMMENDATIONS FOR TRANSPORTERS AS ance. However, many OATP2B1 substrates and inhibitors inter- MEDIATORS OF BIOMARKER DISPOSITION AND act with other hepatic transporters and a clear clinical example of DRUG–VITAMIN INTERACTIONS a hepatic OATP2B1 DDI remains elusive.36 For example, asu- In this section, evidence is presented for the organic anion trans- naprevir, a potent inhibitor of OATP1B1 and OATP2B1, porter, OAT2, as a mediator of the disposition of creatinine, and increased the plasma AUC of rosuvastatin 1.9-fold.37 In addition for the thiamine transporter, THTR2, as a mediator of drug- to OATP1B1, the asunaprevir/rosuvastatin DDI appears to induced vitamin deficiency in certain populations. Finally, an require additional consideration of the role of hepatic OATP2B1 update is presented on key bile acid transporters. for mechanistic explanation. The relative contribution of OATP2B1 to overall hepatic uptake merits assessment when this Organic anion transporter 2 (OAT2) process cannot be otherwise explained. Considerably less attention has been given to the clinical signifi- In summary, OATP2B1 can play a role in intestinal absorption cance of OAT2 (SLC22A7) relative to its SLC22A counterparts, and hepatic clearance of drugs. OAT1/3 (SLC22A6/8) and OCT2 (SLC22A2). Nevertheless, Present clinical evidence is insufficient to recommend prospec- OAT2 has a broad substrate specificity and is highly expressed in tive evaluation of OATP2B1 in drug development. As an emerg- the liver and kidney, making it a likely candidate to be a mediator ing transporter, the role of OATP2B1 should be explored based of clinically relevant DDIs. Particularly intriguing is that OAT2 on evidence of in vivo transport in the intestine or liver that can- is the only SLC22A member highly expressed in the liver with a not be attributed to more common mechanisms (e.g., intestinal bias towards anionic substrates. While suffering from some con- P-gp/BCRP, hepatic OATP1B1/1B3). Intestinal OATP2B1 tradictory findings,48 the main reason OAT2 has not been

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routinely studied during drug development is likely due to the shares a common moiety of 4-aminopyrimidine with thiamine, is lack of an established role as the molecular mechanism for clini- a potent inhibitor of THTR2 but not THTR1, and may have cally significant effects. Although creatinine tubular secretion has interfered with the oral absorption of thiamine resulting in been accepted to be mediated by OCT2 and MATE1/2-K,49 TD.64 Subsequent studies have identified several inhibitors of recent studies suggest that OAT2 may be an important contribu- THTRs.65,66 In particular, the commonly prescribed antibiotic tor to creatinine uptake into the renal proximal tubule.50 OAT2 trimethoprim, which has been associated with TD,68 was found therefore has the potential to play an important role in the deter- to potently inhibit both THTR1 and THTR2 at clinically rele- mination of creatinine clearance, a commonly used clinical bio- vant concentrations.65 In addition to the identification of inhibi- marker of renal function. tors, several drugs have now been identified to be substrates for Substrates of OAT2 include structurally diverse physiologic THTRs. While fedratinib is a substrate of THTR2 only, tri- metabolites, signaling molecules, and drugs. Notably, OAT2 is the methoprim is transported by both THTR1 and THTR2.65 most efficient SLC transporter identified to date for acyclic guano- Although more limited in scope, some substrate overlap has been sine nucleoside analogs (acyclovir, ganciclovir, and penciclo- observed between THTR2 and other xenobiotic cationic trans- vir),48,51–54 cyclic GMP,48,50,51,55 creatinine,48,50 and diclofenac.54 porters, such as OCT1, OCT2, MATE1, and MATE2-K. For OAT2 may play a role in the hepatic clearance of tolbutamide.56 example, prototypical OCT/MATE substrates, metformin, 1- Recently, in vitro studies have identified OAT2 as the most methyl-4-phenylpyridinium (MPP1), and famotidine are also efficient transporter of creatinine, 40-fold more efficient than transported by THTR2.66 OCT2.48,50 Further, the protein expression of OAT2 in the kid- Inhibition of THTR2 may have a significant impact on thia- ney is within 10-fold of OCT2 expression.57,58 Taken together, mine intestinal absorption and renal reabsorption, resulting in these data suggest that OAT2 may contribute to the active tubu- TD. However, in addition to THTR2 inhibition, many other lar secretion of creatinine. Indeed, OAT2 demonstrated predic- factors including malnutrition, reduced gastrointestinal absorp- tive utility for clinical changes in serum creatinine with the tion due to gastric bypass surgery, prolonged vomiting or diar- experimental Janus Kinase 1 inhibitor itacitinib.59 Inhibition of rhea, and chronic alcohol use can cause TD.69 In addition, many OAT2 has also been suggested to play a role in the serum creati- reported cases of drug-induced TD, which ultimately caused WE, nine elevations observed with indomethacin.48 However, a study were due to interruption of the thiamine metabolism pathway. of creatinine excursion mechanisms for 15 drugs suggested that For example, tolazamide, a glucose-lowering drug used for the clinical OAT2 inhibition may be uncommon.60 treatment of type 2 diabetes, and isofamide, a chemotherapeutic Because there is no selective in vivo inhibitor of OAT2, it has agent, have been associated with WE likely caused by their inhibi- been difficult to truly establish the in vivo role of OAT2 in creati- tion of thiamine conversion to thiamine pyrophosphate.70,71 nine disposition. While the broad assessment of OAT2 transport While many drug-induced TD mechanisms are related to thia- and inhibition for drug candidates cannot be recommended at mine metabolism, either directly or indirectly, cases that involve this time, it is a promising candidate for future mechanistic, phar- the inhibition of THTR2 resulting in disruption of thiamine macogenomic, and pharmacologic research. absorption are rather sparse. Although both the [I2]/IC50 and [I1]/IC50 values of fedratinib for THTR2 and trimethoprim for Thiamine transporter 2 (THTR2) both THTR1 and THTR2 exceed the cutoff for a clinical DDI The thiamine transporters (THTR) 1 (SLC19A2) and 2 study (i.e., [I2]/IC50 > 10 and [I1]/IC50 > 1.25, where I2 is the (SLC19A3) are responsible for the oral absorption and tissue dis- intestinal maximal concentration (dose/250 mL) and I1 is the tribution of thiamine (vitamin B1). They are expressed in many unbound systemic Cmax), WE has been observed only with fedra- organs and important physiologic barriers including the intestine, tinib treatment. Fedratinib was tested in patients suffering from blood–brain barrier (BBB), and the kidney proximal tubule.61–63 myelofibrosis, a rare cancer of the bone marrow, while trimetho- While THTR2 is localized on the apical side of enterocytes, and prim is often used for treating bladder and urinary tract infec- kidney proximal tubules, the localization of THTR1 is mainly on tions. Therefore, certain patients who are more vulnerable to the basolateral side.61–63 The tissue distribution and localization vitamin deficiency due to impaired absorption and malnutrition makes THTRs potentially important in thiamine intestinal may be more prone to develop WE than other disease popula- absorption, brain penetration, and renal reabsorption. THTRs tions following treatment with drugs which can affect thiamine have been thought of as highly selective for thiamine until recent absorption and distribution. For example, thiamine deficiency studies demonstrated interactions of THTRs with commonly has been reported to be common in the elderly, individuals who prescribed drugs including metformin and trimethoprim, and abuse alcohol, and in patients who have undergone bariatric sur- suggested potentially clinically relevant consequences due to their gery.72,73 Duration of treatment with a THTR2-inhibitor drug inhibition by the drug candidate fedratinib.64–66 also is a likely risk factor for TD. In addition, a recent study Fedratinib, a Janus Kinase 2 inhibitor, was terminated in phase reported a high rate of thiamine deficiency in patients with mye- III due to the observation of neurological adverse events consis- loproliferative disorders including an increased incidence of tent with Wernicke’s encephalopathy (WE) in eight out of 600 WE74 perhaps making this population more sensitive to an patients.67 The WE reported with fedratinib use may have been inhibitor of thiamine transport like fedratinib. Therefore, moni- due to thiamine deficiency (TD), and were ameliorated in at least toring thiamine concentrations in those vulnerable patient popu- one patient upon thiamine supplementation.67 Fedratinib, which lations during the treatment with THTR2 inhibitors may help

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identify patients at increased risk, and, therefore, prevent the mechanisms.78,82 Several groups have attempted to assess whether onset of drug-induced WE. MRP inhibition in addition to BSEP inhibition increases DILI The incidence of drug-induced vitamin deficiencies may be predictability; however, this resulted in conflicting conclu- underappreciated. Factors affecting the observation of effects on sions.83–85 In addition to bile acids, MRP2, MRP3, and MRP4 nutrients include the lack of specific monitoring and that severe are important determinants of hepatobiliary disposition of polar clinical events may only manifest in sensitive populations with drug metabolites (e.g., glucuronide conjugates), which can con- underlying vitamin deficiency. THTR2 is important in the tribute to overall victim and perpetrator DDI potential.86 absorption and the distribution of thiamine, as well as various The organic solute transporter alpha/beta (OSTa/b), which drugs and xenobiotics. Overall, assessing drug interactions with consists of two gene products encoded by SLC51A and SLC51B, THTR2 in vitro may aid drug developers in predicting which is a bidirectional transporter expressed on the basolateral mem- drugs should be carefully monitored in susceptible populations brane of human hepatocytes, cholangiocytes, and enterocytes.87 for drug-induced thiamine deficiency. Heterodimerization of the two subunits and movement of the complex to the basolateral membrane is required for OSTa/b to Hepatic bile acid transporters transport substrates by facilitated diffusion.88 OSTa/b substrates Several hepatic transporters contribute to the disposition of bile include bile acids, sulfate conjugates of steroid hormones, and acids, and drug interactions involving some of these transporters some drugs.87,89 Hepatic expression of OSTa and OSTb is sig- may cause cholestasis and liver injury. In addition to bile acids, nificantly increased in obstructive cholestasis90 and primary bili- phosphatidylcholine and cholesterol also are important constitu- ary cirrhosis,91 a response that is dependent on regulation by ents of bile. Phosphatidylcholine forms mixed micelles with cho- FXR. Adaptive upregulation of OSTa/b may protect the liver lesterol and bile acids, protecting bile ducts from toxic bile acids. from hepatotoxic bile acids that accumulate in cholestatic condi- This section briefly highlights the key hepatobiliary transporters. tions.92 Recent studies revealed that troglitazone sulfate, a potent Biliary excretion of bile acids is predominantly mediated by BSEP inhibitor, also inhibits taurocholate transport by OSTa/b bile salt export pump (BSEP) (ABCB11), and a separate white (Malinen, in press, 2018). OSTa/b is an emerging compensatory paper dedicated to BSEP inhibition as a mechanism of drug- basolateral efflux transporter that functions much like a “safety- induced liver injury (DILI) is published in this issue of CPT. valve” to protect the liver from toxic concentrations of bile acids. Clinically, rare mutations that result in farnesoid X receptor Inhibition of OSTa/b is a potential, but understudied, mecha- (FXR) deficiency and undetectable BSEP expression can cause nism that may contribute to bile acid-mediated DILI. rapidly progressive cholestatic liver injury.75 Although BSEP inhi- Multidrug resistance-associated protein 2 (MRP2, ABCC2) bition has been linked to intrahepatic accumulation of bile acids, mediates the biliary excretion of glucuronide and sulfate conju- which can trigger clinical cholestasis and may lead to DILI, it is gates of bile acids (e.g., sulfated tauro- or glycolithocholate), difficult to prospectively link in vitro inhibition of BSEP with endogenous compounds (e.g., bilirubin glucuronides), and xeno- clinical hepatotoxicity. In addition to BSEP, other hepatic uptake biotics. Dubin–Johnson syndrome, genetic deficiency of MRP2, and efflux transporters contribute to bile acid hepatobiliary dis- is characterized by hyperbilirubinaemia. Although total serum position. Sodium taurocholate cotransporting polypeptide bile acid concentrations are unaffected in Dubin–Johnson (NTCP), a solute carrier protein (SLC10A1) expressed on the patients,93 hepatocyte and systemic concentrations of individual basolateral membrane of hepatocytes, is primarily responsible for bile acid species may be altered. Inhibition of MRP2 may result hepatic uptake of bile acids in humans. Many BSEP inhibitors in hepatocellular accumulation of toxic metabolites, which may can also inhibit NTCP-/OATP-mediated hepatic uptake of bile contribute to DILI.94 Studies95 suggest that genetic variations in acids,76 which may result in increased systemic concentrations of MRP2 may increase susceptibility to herb- and drug-induced liver bile acids. This overlap in bile acid uptake/efflux inhibition may injury. Alterations in MRP2 expression or function may impact serve as a protective mechanism to prevent potentially toxic accu- the hepatobiliary disposition of bile acids and hepatotoxic drugs, mulation of bile acids in the liver.77 and could be a contributing factor in DILI. Multidrug resistance proteins 3 and 4 (MRP3, MRP4) are Biliary secretion of phosphatidylcholine is mediated by multi- ATP-dependent efflux pumps localized to the sinusoidal mem- drug resistance protein 3 (MDR3, ABCB4).96 Mice lacking brane that mediate the transport of substrates from the hepato- Mdr2, the mouse ortholog of MDR3, exhibit impaired biliary cyte into blood. MRP3 (ABCC3) and MRP4 (ABCC4) are secretion of phosphatidylcholine and develop hepatobiliary dis- induced under cholestatic conditions, leading to the hypothesis ease.97 In humans, genetic polymorphisms resulting in MDR3 that these transporters can serve as a compensatory mechanism deficiency lead to cholestatic disorders.98,99 Inhibitory effects of to alleviate increases in intracellular bile acid concentrations drugs on MDR3 have not been extensively investigated, but sev- when biliary excretion is impaired.78,79 Increases in liver bile acids eral studies support the potential role of MDR3 inhibition in and liver toxicity were observed in bile duct ligated Mrp4- DILI. Itraconazole, which induced cholestatic liver injury in knockout mice, but not Mrp3-knockout mice.80,81 Direct human patients, inhibits MDR3.100 Screening of 125 drugs demon- translation of data obtained from preclinical bile acid disposition strated that MDR3 clinical inhibition potency may help differen- studies can be challenging due to species differences in the bile tiate hepatotoxic drugs and nonhepatotoxic drugs.101 In addition, acid pool, the relative contribution of various mechanisms to combined analysis of BSEP and MDR3 inhibition data showed overall bile acid hepatobiliary disposition, and regulation of those that nine compounds potently inhibited both MDR3 and BSEP

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(IC50 < 20 lM), all of which were classified as drugs with the connection with material reported herein is not to be construed as either highest DILI incidence.101 an actual or implied endorsement of such products by the FDA. As reviewed in this section, the physiology of bile acid disposition is complex, with involvement of multiple hepatic transport- FUNDING ers in addition to BSEP (ABCB11). Moreover, bile acids undergo No funding was received for this work. extensive enterohepatic recirculation and are metabolized by enzymes in hepatocytes, intestinal epithelial cells, and by the gut CONFLICT OF INTEREST microbiome. The first step in bile acid reabsorption is mediated The authors declare no competing interests for this work. by intestinal apical sodium-dependent bile transporter (ASBT, a.k.a. IBAT), which is not specifically discussed, as it is not a VC 2018 American Society for Clinical Pharmacology and Therapeutics mechanism of cholestasis, but whose inhibition may warrant consideration upon observation of impaired bile acid absorption. 1. International Transporter, C. et al. Membrane transporters in drug development. Nat. Rev. Drug Discov. 9, 215–236 (2010). Hepatic bile acid levels are regulated through FXR-SHP and 2. Zamek-Gliszczynski, M.J., Giacomini, K.M. & Zhang, L. Emerging FXR-FGF19 pathways, which control multiple adaptation mech- clinical importance of hepatic organic cation transporter 1 (OCT1) in anisms (e.g., decrease in CYP7A1, the rate-limiting step in bile drug pharmacokinetics, dynamics, pharmacogenetic variability, and acid synthesis, induction of sinusoidal efflux transporters, induc- drug interactions. Clin. Pharmacol. Ther. (2017) [Epub ahead of 102 print]. tion of conjugating enzymes and BSEP). Systematic under- 3. Hibma, J.E. et al. 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Genetic polymorphisms in organic cation transporter 1 attenuates hepatic metformin exposure in humans. OCT2 and MATEs. The proposed evaluation approach for Clin. Pharmacol. Ther. 102, 841–848 (2017). OCT1 substrates and inhibitors follows principles established for 7. Cho, S.K., Kim, C.O., Park, E.S. & Chung, J.Y. Verapamil decreases hepatic OATP1B1 and OATP1B3 (Figure 2), although specific the glucose-lowering effect of metformin in healthy volunteers. Br. J. Clin. Pharmacol. 78, 1426–1432 (2014). cutoff values necessitate further study and refinement. Both intes- 8. Wittwer, M.B. et al. Discovery of potent, selective multidrug and tinal and hepatic drug uptake via OATP2B1 should be evaluated toxin extrusion transporter 1 (MATE1, SLC47A1) inhibitors through retrospectively in instances of DDIs, drug–food interactions, or prescription drug profiling and computational modeling. J. Med. Chem. 56, 781–795 (2013). disposition otherwise unexplained by more common mecha- 9. Zamek-Gliszczynski MJ, Chu X, Cook JA, Custodio JM, Galetin A, nisms. Evidence to justify the evaluation of brain OATP1A2 and Giacomini KM, Lee CA, Paine MF, Ray AS, Ware JA, Wittwer MB, renal OATP4C1 with a high level of concern from a DDI per- Zhang L; International Transporter Consortium. ITC Commentary on Metformin Clinical Drug-Drug Interaction Study Design That Enables spective is lacking. THTR2 may be relevant in the context of pre- an Efficacy- and Safety-Based Dose Adjustment Decision. Clin existing thiamine deficiency, and, therefore, should be considered Pharmacol Ther. 2018 May 15. doi: 10.1002/cpt.1082. [Epub for drugs used in sensitive populations or when evidence of drug- ahead of print] 10. Yee SW, Brackman DJ, Ennis EA, Sugiyama Y, Kamdem LK, induced thiamine deficiency is observed. This article highlights Blanchard R, Galetin A, Zhang L, Giacomini KM. Influence of the emerging importance of OAT2 as a mechanism of creatinine Transporter Polymorphisms on Drug Disposition and Response: A renal secretion, but relevance to drug development is not suffi- Perspective From the International Transporter Consortium.Clin Pharmacol Ther. 2018 Apr 21. doi: 10.1002/cpt.1098. [Epub ciently well established to support specific recommendations. ahead of print] Transporters involved in bile acid disposition are not specifically 11. Tzvetkov, M.V. et al. Increased systemic exposure and stronger recommended for evaluation with a high level of concern from a cardiovascular and metabolic adverse reactions to fenoterol in individuals with heritable OCT1 deficiency. Clin. Pharmacol. Ther., DDI perspective, but may be considered in cholestasis/DILI. (2017) [Epub ahead of print]. 12. Stamer, U.M., Musshoff, F., Stuber, F., Brockmoller, J., Steffens, M. & Tzvetkov, M.V. Loss-of-function polymorphisms in the organic cation transporter OCT1 are associated with reduced postoperative ACKNOWLEDGMENTS tramadol consumption. Pain 157, 2467–2475 (2016). We thank Drs. Aleksandra Galetin, Shiew-Mei Huang, Vikram Arya, 13. Tzvetkov, M.V., Saadatmand, A.R., Lotsch, J., Tegeder, I., Stingl, and Xinning Yang for review of the article prior to submission . JDU was J.C. & Brockmoller, J. Genetically polymorphic OCT1: another piece supported in part by a grant from NIDA P01 DA032507. in the puzzle of the variable pharmacokinetics and pharmacodynamics of the opioidergic drug tramadol. Clin. Pharmacol. Ther. 90, 143–150 (2011). DISCLAIMER 14. Tzvetkov, M.V., Saadatmand, A.R., Bokelmann, K., Meineke, I., The contents of this article reflect the views of the authors and should Kaiser, R. & Brockmoller, J. Effects of OCT1 polymorphisms on the not be construed to represent the FDA’s views or policies. No official sup- cellular uptake, plasma concentrations and efficacy of the 5-HT(3) port or endorsement by the FDA is intended or should be inferred. The antagonists tropisetron and ondansetron. Pharmacogenomics J. 12, mention of commercial products, their sources, or their use in 22–29 (2012).

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