Drug–Drug Interaction Studies: Regulatory Guidance and An Industry Perspective

Prueksaritanont, Thomayant; Chu, Xiaoyan; Gibson, Christopher R; Cui, Donghui; Yee, Ka Lai; Ballard, Jeanine; Cabalu, Tamara D.; Hochman, Jerome H.

doi:10.1208/s12248-013-9470-x

Cited by 204 publications

(164 citation statements)

References 84 publications

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“…In this regard, CAF may alter APAP pharmacokinetic (PK) processes at the organism level8, 11 and may influence APAP‐induced pharmacodynamic (PD) responses at the cellular scale 10. In this context, CAF and APAP may thus be considered as perpetrator and victim drug, respectively 12. Notably, the unintentional co‐administration of CAF together with other drugs is mostly unavoidable, because coffee is one of the most popular drinks in the world.…”

Section: Figurementioning

confidence: 99%

Multiscale modeling reveals inhibitory and stimulatory effects of caffeine on acetaminophen‐induced toxicity in humans

Thiel

Cordes

Baier

et al. 2017

CPT Pharmacom & Syst Pharma

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Acetaminophen (APAP) is a widely used analgesic drug that is frequently co‐administered with caffeine (CAF) in the treatment of pain. It is well known that APAP may cause severe liver injury after an acute overdose. However, the understanding of whether and to what extent CAF inhibits or stimulates APAP‐induced hepatotoxicity in humans is still lacking. Here, a multiscale analysis is presented that quantitatively models the pharmacodynamic (PD) response of APAP during co‐medication with CAF. Therefore, drug‐drug interaction (DDI) processes were integrated into physiologically based pharmacokinetic (PBPK) models at the organism level, whereas drug‐specific PD response data were contextualized at the cellular level. The results provide new insights into the inhibitory and stimulatory effects of CAF on APAP‐induced hepatotoxicity for crucially affected key cellular processes and individual genes at the patient level. This study might facilitate the risk assessment of drug combination therapies in humans and thus may improve patient safety in clinical practice.

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Section: Figurementioning

confidence: 99%

Multiscale modeling reveals inhibitory and stimulatory effects of caffeine on acetaminophen‐induced toxicity in humans

Thiel

Cordes

Baier

et al. 2017

CPT Pharmacom & Syst Pharma

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“…51,52 Most clinical evaluations appropriately focus on DDIs related to the payload. After release from the ADC, the payload may be metabolized by cytochrome P450 (CYP450) and/or UDP glucuronosyltransferase enzymes and is at risk of DDIs with any coadministered inducers or inhibitors of these systems.…”

Section: Drug-drug Interaction Assessmentmentioning

confidence: 99%

Antibody–Drug Conjugates as Cancer Therapeutics: Past, Present, and Future

Vezina

Cotreau

Han

et al. 2017

The Journal of Clinical Pharma

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Antibody-drug conjugates (ADCs) represent an innovative therapeutic approach that provides novel treatment options and hope for patients with cancer. By coupling monoclonal antibodies (mAbs) to cytotoxic small-molecule payloads with a plasma-stable linker, ADCs offer the potential for increased drug specificity and fewer off-target effects than systemic chemotherapy. As evidence for the potential of these therapies, many new ADCs are in various stages of clinical development. Because their structure poses unique challenges to pharmacokinetic and pharmacodynamic characterization, it is critical to recognize the differences between ADCs and conventional chemotherapy in the design of ADC clinical development strategies. Although some properties may be determined mainly by either the mAb or the small-molecule portion, the behavior of these agents is not always predictable. Furthermore, because the absorption, distribution, metabolism, and excretion (ADME) of ADCs are influenced by all 3 of its components (mAb, linker, and payload), it is important to characterize the intact molecule, any target-mediated catabolic clearance of the mAb, and the ADME properties of the small-molecule payload. Here we describe key issues in the clinical development of ADCs, including considerations for designing first-in-human studies for ADCs. We discuss some difficulties of ADC pharmacokinetic characterization and current approaches to overcoming these challenges. Finally, we consider all aspects of clinical pharmacology assessment required during drug development, using examples from the literature to illustrate the discussion.

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“…This has recently led drug regulatory agencies to edict recommendations for the characterization of putative interactions of new molecular entities with some of the major hepatic drug transporters [6]. In this context, accurate characterization of molecular and cellular pathways controlling expression and activity level of hepatic drug transporters is likely an important issue.…”

Section: Introductionmentioning

confidence: 99%

Protein kinase C-dependent regulation of human hepatic drug transporter expression

Mayati

Vée

Moreau

et al. 2015

Biochemical Pharmacology

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Hepatic drug transporters are now recognized as major actors of hepatobiliary elimination of drugs. Characterization of their regulatory pathways is therefore an important issue. In this context, the present study was designed to analyze the potential regulation of human hepatic transporter expression by protein kinase C (PKC) activation. Treatment by the reference PKC activator phorbol 12-myristate 13-acetate (PMA) for 48h was shown to decrease mRNA expression of various sinusoidal transporters, including OATP1B1, OATP2B1, NTCP, OCT1 and MRP3, but to increase that of OATP1B3, whereas mRNA expression of canalicular transporters was transiently enhanced (MDR1), decreased (BSEP and MRP2) or unchanged (BCRP) in human hepatoma HepaRG cells. The profile of hepatic transporter mRNA expression changes in PMA-treated HepaRG cells was correlated to that found in PMA-exposed primary human hepatocytes and was similarly observed in response to the PKC-activating marketed drug ingenol mebutate. It was associated with concomitant repression of OATP1B1 and OATP2B1 protein expression and reduction of OATP, OCT1, NTCP and MRP2 activity. The use of chemical PKC inhibitors further suggested a contribution of novel PKCs isoforms to PMA-mediated regulations of transporter mRNA expression. PMA was finally shown to cause epithelial-mesenchymal transition (EMT) in HepaRG cells and exposure to various additional EMT inducers, i.e., hepatocyte growth factor, tumor growth factor-1 or the HNF4 inhibitor BI6015, led to transporter expression alterations highly correlated to those triggered by PMA. Taken together, these data highlight PKC-dependent regulation of human hepatic drug transporter expression, which may be closely linked to EMT triggered by PKC activation.

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Drug–Drug Interaction Studies: Regulatory Guidance and An Industry Perspective

Cited by 204 publications

References 84 publications

Multiscale modeling reveals inhibitory and stimulatory effects of caffeine on acetaminophen‐induced toxicity in humans

Multiscale modeling reveals inhibitory and stimulatory effects of caffeine on acetaminophen‐induced toxicity in humans

Antibody–Drug Conjugates as Cancer Therapeutics: Past, Present, and Future

Protein kinase C-dependent regulation of human hepatic drug transporter expression

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