PBPK modeling solutions as a potential risk mitigation strategy for pH dependent DDIs

Clinical Pharmacology, Modeling and Simulation (CPMS), Parexel International

Drug-Drug Interaction (DDI) is a crucial aspect in new drug development due potential impact on patients’ safety. Pharmacokinetic interactions at the level of absorption, distribution, metabolism and elimination should be considered in any clinical pharmacology submission for regulatory approval.¹

At the absorption level, drug solubility and permeability are two prerequisites for systemic absorption of immediate-release oral drugs. If the newly developed drug showed pH sensitive solubility in the physiological pH range of the gastrointestinal tract (as is the case of poorly soluble weakly acidic and weakly basic drugs of BCS Class IIa and IIb, respectively), it is very likely that its absorption will be impacted by the concomitant administration of an acid-reducing agent (ARA) that elevates the gastric pH. ARAs are prescribed to alleviate symptoms of gastroesophageal reflux disease and many are available over the counter. They are classified according to their mechanism of action, into three categories: 1) proton pump inhibitors (PPIs) e.g. omeprazole, 2) H2-receptor antagonists e.g. famotidine and 3) antacids e.g. magnesium hydroxide. Some of these ARAs, at therapeutic doses, can raise gastric pH from 1-2 (normal gastric pH) to above 6.0.² The pH elevation can lead to undesirable clinical consequences; either reduced efficacy (due to lower blood levels) of concomitantly administered weakly basic drugs or in the case of weakly acidic drugs, ARAs can cause higher systemic exposure and expose the patient to more adverse drug events if the drug exhibits a steep exposure -response relationship. The risk of clinically significant DDIs induced by elevated gastric pH is widely known as pH dependent DDIs or ARA DDIs.

Physiologically based pharmacokinetic (PBPK) modelling and simulation which comprises physiological parameters (blood flow, tissue volume, partition coefficients, etc), along with key physicochemical properties of the drug (chemical structure, ionization constant (pKa), solubility/dissolution as a function of pH, permeability, lipophilicity (log P)), and the drug dose can be used to proactively assess or preclude potential DDIs with ARAs and to estimate these interactions qualitatively and quantitatively. PBPK modeling was used to evaluate and predict the direction (i.e., positive or negative) and the magnitude of ARA DDIs of four weakly basic drugs.³ PBPK modeling was also employed in the mechanistic understanding of drug absorption when confounded conditions exist by integrating biorelevant media (FaSSIF and FeSSIF) to mimic fasted/fed gastric conditions under PPIs therapy to predict PPI effects in absence and presence of food.⁴

FDA has recently released a draft guidance⁵ on ‘Evaluation of Gastric pH-Dependent Drug Interactions with Acid-Reducing Agents: Study Design, Data Analysis, and Clinical Implications’ to address the issue of ARA DDIs and safeguard population health. In a stepwise manner, starting with in-vitro measurements, the guidance laid a roadmap to evaluate pH dependent DDI liability, provided insights into clinical study design and risk mitigation strategies and proposed a framework to evaluate pH dependent DDI risk for weakly basic drugs in immediate release oral formulation. Moreover, the guidance discussed the use of modeling approaches for example PBPK models, and advised a decision tree for determining if a clinical study is needed, when in vitro data is not predictive of fed pH effect, and conditions for extrapolating the results of a potent PPI clinical study to labeling of concomitant usage of less potent ARAs.

Parexel CPMS scientists can help you with your drug development program by performing feasibility study and potential PBPK models to proactively determine pH dependent DDI liability and waive/inform clinical ARA -DDI study.

Parexel’s Clinical Pharmacology, Modeling and Simulation team encompasses approximately 33 scientists and analysts from around the globe.  Our expert pharmacometricians are well poised to assist companies in the development, validation, and application of physiologically based pharmacokinetic modeling.  For further information, contact Joseph Kim, PhD, RPh, VP, Clinical Pharmacology, Modeling and Simulation.

References:

1. Guideline on the Investigation of Drug Interactions. 21 June 2012, CPMP/EWP/560/95/Rev. 1 Corr. 2**
2. Zhang et., 2014. Clin Pharmacol Ther. 96(2):266-77.
3. Dong et al., 2020. CPT Pharmacometrics Syst Pharmacol. 9(8):456-465.
4. Dodd et al., 2019. J Pharm Sci. 108(1):87-101.
5. Evaluation of Gastric pH Dependent Drug Interactions with Acid-Reducing Agents: Study Design, Data Analysis, and Clinical Implications. Guidance for Industry. CDER, Nov 2020 at: https://lnkd.in/gKd9ch2

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