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Clinical Probes and Endogenous Biomarkers as Substrates for Transporter Drug-Drug Interaction Evaluation

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Perspectives From the International Transporter Consortium

Introduction

Transporter studies are performed at various stages of drug development ‒ discovery to first-in-human (FIH) phase (in-vitro substrate and inhibition studies), FIH to proof of concept (POC) phase (clinical DDIs), and POC to new drug application (NDA)/post-marketing phase (product labeling and post-marketing surveillance). Currently, in-vitro transporter inhibition assays are conducted to determine the risk for potential clinical DDIs.

During clinical DDI studies, an appropriate probe substrate is selected to tease out the effect of NME inhibition of a transporter, to understand the mechanism of the DDI, and enable extrapolation to other drugs, leading to appropriate product labeling. Due to multiple factors, including the limitations of IVIVE, an overlap of substrate/inhibition for enzymes and transporters, multiple drug binding sites on transporters, and the fact that organ-specific changes in drug exposure may not be reflected in systemic PK, this strategy may result in false-positive and false-negative outcomes.

Instead of using a drug as a clinical probe substrate, a validated endogenous biomarker offers the potential for evaluating NMEs as transporter inhibitors in early clinical studies (by reanalyzing already-collected PK samples), without the need for dedicated clinical DDI studies. A list of desirable characteristics for biomarkers for this purpose are summarized in Table 1.

Based on the above characteristics and data generated so far, ITC has compiled a list of suitable probe substrates and biomarkers to study transporter-related clinical DDIs (Table 2).

Biomarkers listed in the above table are additionally transported by MRP2 and MRP3 (CPI, CPIII, CB), OATP2B1 (CPIII), OAT1 (HDA, TDA), OAT3 (GCDCA-S, HAD, TDA) or NTCP (GCDCA-S), thus reducing their selectivity.

As a perpetrator drug may inhibit multiple transporters, a probe drug cocktail approach has been tested in vitro and in clinics. Examples of cocktails successfully tested are shown in Table 3.

Key Takeaways:

  • ITC proposed the following workflow for the identification, characterization, and validation of an endogenous biomarker
  • ITC proposed the following decision tree for incorporating endogenous biomarkers and probe drugs to assess transporter-related inhibition during drug development

References

  1. Chu XLiao MShen HYoshida KZur AAArya VGaletin AGiacomini KMHanna IKusuhara HLai YRodrigues DSugiyama YZamek-Gliszczynski MJZhang LInternational Transporter Consortium. Clinical Probes and Endogenous Biomarkers as Substrates for Transporter Drug-Drug Interaction Evaluation: Perspectives From the International Transporter Consortium. Clin Pharmacol Ther.2018, 104(5):836-864
  2. Müller FSharma AKönig JFromm MF. Biomarkers for in vivo assessment of transporter function. Pharmacol Rev. 2018, 70(2): 246-277
  3. Webinar presented by Dr. Zamek-Gliszczynski, Senior Fellow and Director, DMPK, GlaxoSmithKline https://www.absorption.com/kc/transporter-webinar/
  4. Absorption Systems’ Transporter Reference Guide, 2018, 4th Edition, Absorption Systems https://www.absorption.com/kc/transporter-reference-guide-4th-edition-download/

Monitoring Oral Solid Dosage Forms Quality by NIR Spectroscopy and IDAS2

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Monitoring Oral Solid Dosage Forms Quality by NIR Spectroscopy and IDAS2

Johayra Simithy1, Carlos Jiménez-Romero1, Anthony Severdia2, Daniel Álvarez3, Manuel Grosso1, Antonio Arias1,
Nicole Spivey2, Jibin Li2,  Pablo N. Solís3, and Ismael J. Hidalgo1,2
1Absorption Systems Panama, Inc, Panama City, Panama; 2Absorption Systems LP, Exton, Pennsylvania, USA; 3Laboratorios MEDIPAN S.A., Panama City, Panama

This poster was presented at CRS, July 2019

Regulatory agencies in developing countries often struggle to assure the quality, safety and efficacy of drugs and one concern is that unreported changes in formulation excipients or manufacturing processes can alter product performance. The present work proposed an analytical strategy for distinguishing between standard (reference) and modified oral solid dosage forms for two drugs: acyclovir and amlodipine, through the combined use of near-infrared (NIR) spectroscopy and chemometrics, as a first step towards the development of approaches to identify lot-to-lot changes of registered products; followed by evaluating in vitro dissolution and permeation of drug dosage forms using a newly developed in vitro dissolution absorption system (IDAS2). For this purpose, tablets of acyclovir 400 mg (Virax®) and amlodipine 5 mg (Amlopin®) with deliberate modifications in the percentage of active pharmaceutical ingredient (API) or the individual excipients were manufactured.

Dabigatran Etexilate and Digoxin: Comparison as Clinical Probe Substrates for Evaluation of P-gp Inhibition

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Introduction
P-glycoprotein (P-gp) is a drug transporter recommended by regulatory agencies for in-vitro and in-vivo DDI evaluation. Due to high inter-laboratory variability in in-vitro P-gp data, regulators have recommended using two in-vitro test systems for assessing potential DDIs involving the transporter. As P-gp is expressed in multiple sites in the body (intestine, liver, kidney, blood-brain barrier), a probe substrate whose disposition is dependent on P-gp in a given organ should be selected for clinical DDI studies to evaluate changes in exposure involving that organ. Typically, a probe substrate is chosen to decipher a significant fold change in plasma exposure (AUC, Cmax) with and without inhibitor to assess a potential DDI. Dabigatran Etexilate (DE) and digoxin have been screened as clinical probe substrates for studying DDIs involving intestinal P-gp. Table 1 shows examples of some P-gp inhibitors that were studied with both DE and digoxin as probe substrates.

Although amiodarone and dronedarone showed similar fold change in AUC of dabigatran and digoxin, cobicistat and glecaprevir/pibrentasvir showed higher AUC fold change with dabigatran than with digoxin. Dabigatran is even more sensitive at a subtherapeutic (micro) dose, which results in a gut concentration close to its Km for P-gp. In this commentary, ITC suggested selecting a probe substrate based on the question to be answered.

 Ideal Clinical Probe Substrate Characteristics for P-gp DDI Studies

  • Highly selective – transported by P-gp only
  • Stable – No or minimal biotransformation
  • Sensitive – Low to moderate fraction absorbed
  • Tolerability – Have sufficient safety margin to cover an increase in exposure with a P-gp inhibitor
  • Ease of analysis – Availability of standards and suitable analytical method

Key Takeaways:

  1. Selection of clinical probe substrate should be based on the specific DDI questions to be addressed; e.g., digoxin for renal P-gp inhibition or to determine the safety of a comedication specifically with digoxin, and DE for intestinal P-gp inhibition.
  2. Digoxin clinical studies may still be warranted in spite of its narrow therapeutic index. To also assess the impact on renal P-gp, calculation of renal clearance is recommended.
  3. Microdose of DE (375 µg) more sensitive for assessing intestinal P-gp DDI. Assess a potential perpetrator as an inhibitor of CES beforehand.
  4. Good IVIVC with DE: IC50 values for several P-gp inhibitors based on DE basolateral-to-apical transport predicted the risk of DDIs with no false negatives.

Metformin Clinical DDI Study Design That Enables an Efficacy- and Safety-Based Dose Adjustment Decision

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Introduction
Metformin is an orally administered drug prescribed for the treatment of Type 2 diabetes. It is known to decrease hepatic glucose production, by inhibiting gluconeogenesis, and to increase glucose utilization. Metformin is cationic at physiological pH, is not metabolized, has poor passive permeability, and is excreted unchanged in the urine. OCT1 mediates its hepatic uptake, and its renal clearance is mediated by OCT2, MATE1, and MATE2-K (Figure 1). Metformin is taken along with food to avoid gastrointestinal side effects. Care is also taken not to administer metformin in patients with hepatic or renal impairment as it may lead to lactic acidosis through the inhibition of hepatic glucose production from lactate. Drugs inhibiting OCTs and MATEs could decrease the elimination of metformin and increase its plasma concentration, leading to an elevated risk of metformin-associated lactic acidosis (MALA).

The Dichotomy
Regulatory agencies recommend clinical DDI studies for drugs that are inhibitors of OCT2, MATE1, and/or MATE2-K. A change in systemic exposure of metformin has been monitored as a clinical endpoint in such studies. It has been reported that in spite of unaltered systemic pharmacokinetics of metformin, altered hepatic exposure and antihyperglycemic effect have been observed. On the other hand, increased systemic exposure of metformin did not impact hepatic exposure and efficacy. Based on the clinical evidence, ITC has now recommended considering both pharmacokinetic (PK) and pharmacodynamic (PD) endpoints for deciding on metformin dosing during co-medication with a new molecular entity (NME).

Proposed Metformin DDI Study Design
The following endpoints should be considered for rational dose adjustment of metformin during clinical studies.

  1. Systemic pharmacokinetics (AUC, CmaxHalf-life, V/F, CL/F) : no-effect boundary (0.8-1.25)
  2. Renal clearance: no-effect boundary (0.8-1.25)
  3. Antihyperglycemic effect (oral glucose tolerance test, OGTT): no-effect boundary (0.75-1.33)
  4. Blood lactate concentration (not clinically validated): no-effect boundary not defined yet.

Modeling and Simulation in Metformin DDI Study Design
Physiologically based PK models of metformin are being refined by incorporating efficacy and tissue concentration data for better prediction of clinical DDI outcomes.

Pharmacogenetic Considerations
Transporters involved in the disposition of metformin exhibit polymorphisms, including functionally deficient phenotypes. This may be one of the reasons for pharmacokinetic variability. Hence, a crossover study design is recommended. Where possible, incorporation of genotyping data of study subjects would help in understanding outliers.

Key Takeaways

  • The metformin DDI study design recommended by ITC, incorporating PK and PD assessments, is worth considering.
  • Results from a DDI study involving metformin should not be extrapolated to other drugs, as they are unlikely to predict metformin liver distribution and the resulting efficacy and safety.
  • In a clinical DDI study with dolutegravir (an OCT2 inhibitor) and metformin [1], only metformin systemic exposure was determined (an increase was observed). As renal clearance (a more direct index of OCT2 function) and PD endpoints (reflecting the possible involvement of OCT1 inhibition) were not assessed, a clear dosing recommendation was not possible because the observed DDI could not be explained on the basis of the limited data that was collected.
  • In a clinical DDI study with famotidine (a MATE1 inhibitor) and metformin [1], the determination of both PD parameters (consistent with an increase in hepatic exposure) and PK parameters (increase in both intestinal absorption and renal clearance, resulting in no change in systemic exposure) revealed a complex interaction that would otherwise have been missed.

References

  1. Zamek-Gliszczynski MJChu XCook JACustodio JM, Galetin AGiacomini KMLee CAPaine MFRay ASWare JAWittwer MBZhang L. ITC Commentary on Metformin Clinical Drug-Drug Interaction Study Design That Enables an Efficacy- and Safety-Based Dose Adjustment Decision. Clin Pharmacol Ther. 2018; 104(5):781-784. https://www.absorption.com/kc/transporter-webinar/
  2. Webinar presented by Dr. Zamek-Gliszczynski, Senior Fellow and Director, DMPK, GlaxoSmithKline
  3. Absorption Systems’ Transporter Reference Guide, 2018, 4th Edition, Absorption Systems

Transporters In Drug Development Based On Recent ITC Recommendations

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Introduction

Transporters are membrane proteins highly expressed in various organs of humans. They play a pivotal role in the absorption and disposition of both endogenous and exogenous molecules. In the last decade, a lot of focused research has been conducted to understand potential clinical drug-drug interactions mediated by transporters. Regulatory agencies (including the US FDA and EMA) made mandatory the assessment of new drugs as substrates and inhibitors of drug transporters. Recently, the International Transporter Consortium (ITC) updated their recommendations through a series of white papers based on the latest research. This article discusses the importance of emerging transporters of clinical relevance.

Transporters of Clinical Relevance: The updated recommendations of the ITC for transporter screening by organ, considering drug-drug interaction potential, liver toxicity, drug-induced vitamin deficiency, and disposition of biomarkers, are presented below.

OCT1 is responsible for the hepatic uptake of metformin and its subsequent pharmacological effect.  Therefore, inhibition of OCT1 can greatly impact metformin pharmacodynamics (but not its pharmacokinetics, since it is eliminated almost exclusively by the kidney). Based on clinical evidence, evaluation of substrate and inhibition potential for OCT1 is suggested during drug development as per the decision trees shown below.

OATP2B1 has low- and high-affinity binding sites and is expressed in the intestine and liver. Notable clinical substrates of OATP2B1 are atorvastatin and rosuvastatin. OATP2B1 shows pH-dependent transport. Hence, in addition to screening at pH 7.4, it is also recommended to screen substrates at pH 5.5.

OAT2 is expressed in the liver and kidney. Recent studies have shown that OAT2 is responsible for uptake of creatinine (a renal function biomarker) into the renal proximal tubule. As there is no selective inhibitor of OAT2 in vivo, it is difficult to clearly establish the role of OAT2 in creatinine disposition.

Thiamine Transporters (THTR) 1 and 2 are responsible for uptake and distribution of thiamine (vitamin B1) and are expressed in the intestine, blood-brain barrier, and kidney proximal tubule. THTRs interact with drugs like metformin, trimethoprim, and fedratinib. Inhibition of THTR2 has a significant impact on thiamine intestinal absorption and renal reabsorption, resulting in thiamine deficiency. Many reported cases of drug-induced thiamine deficiency, which ultimately caused Wernicke’s encephalopathy, were due to inhibition of the thiamine disposition pathway.

Hepatic bile acid transporters (BSEP, NTCP, MRP2, MRP3, MRP4, & OST α/β) contribute to the disposition of bile acids, and drug interactions involving these transporters may cause cholestasis and liver injury. Hepatic bile acid levels are regulated through FXR-SHP and FXR-FGF19 pathways, which control multiple adaptive mechanisms for bile acid detoxification.  Another transporter, ASBT, is responsible for reabsorption of bile acids from the intestine and its inhibition is not involved in cholestasis.

Summary

In addition to the transporters (P-gp, BCRP, OAT1, OAT3, OCT2, MATE1, MATE2-K, OATP1B1, and OATP1B3) recommended by regulatory agencies for screening, the following transporters may also be considered: OCT1 & OATP2B1.

  • Clinical evidence has emerged for screening OCT1 for substrates and inhibitors
  • Uptake by OATP2B1 may be evaluated for unexplained mechanisms of possible drug-drug interactions
  • Assessing drug interactions with THTR2 in vitro to enable monitoring of thiamine deficiency in susceptible populations
  • OAT2 as a mechanism of creatinine renal secretion
  • Mechanistic understanding of drug effects on multiple transporters involved in bile acid homeostasis, in addition to BSEP inhibition

References

  1. Zamek-Gliszczynski MJTaub MEChothe PPChu XGiacomini KMKim RBRay ASStocker SLUnadkat JDWittwer MBXia CYee SWZhang LZhang YInternational Transporter Consortium. Transporters in drug development: 2018 ITC recommendations for transporters of emerging clinical importance. Clin Pharmacol Ther. 2018. 104(5): 890-899
  2. Webinar presented by Dr. Zamek-Gliszczynski, Senior Fellow and Director, DMPK, GlaxoSmithKline
  3. Absorption Systems’ Transporter Reference Guide, 2018 4th Edition, Absorption Systems,
  4. In Vitro Metabolism- and Transporter- Mediated Drug-Drug Interaction Studies Guidance for Industry, USFDA, October 2017, https://www.fda.gov/regulatory-information/search-fda-guidance-documents/vitro-metabolism-and-transporter-mediated-drug-drug-interaction-studies-guidance-industry
  5. Guideline on the investigation of drug interactions, EMA, January 2013, https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-investigation-drug-interactions_en.pdf