pH Dependent Drug Interactions with Acid Reducing Agents

Do I Need to Conduct a Clinical Study?

Well the answer is, that it depends on certain characteristics of your investigational drug.

For immediate release basic drugs that has pH dependent solubility at pH of 1.0-6.8, this can mean that solubility in the stomach can decrease as pH increases. When solubility of the investigational drug is lower than the clinical dose/250mL at pH 6.0-6.8 this can reduce solubility at higher pH levels resulting in a potential gastric pH dependent interaction. In the case these criteria are met, one can also test the dissolution profiles in vitro at various pHs. For investigational drugs which have similar dissolution profiles under different pH conditions, it would seem unlikely that there will be a drug interaction with acid reducing agents. However, if there is a difference in dissolution profiles across the pH range or this is not studied a clinical study would be warranted.

For immediate release acidic drugs less information is know, however, for investigational drugs with low solubility at pH 1.0-2.0 an increase in pH could lead to an increase in solubility and thus increase the exposure. Thus the need for a clinical study depends on the safety profile of the investigational drug.

For modified or slow release drugs, the guidance is less clearcut. In some instances in the case of pH-senistive release mechanisms there may be a potential drug interacation with acid reducing agents. If there is a potential for pH to impact the pharmacokinetics of the investigational drug the sponsor should conduct an in vivo study to evaluate the potential interaction.

Study Design

A single dose of the investigational drug in healthy volunteer study designed in a crossover manner can allow evaluation of a potential interaction with acid reducing agents in general unless there are specific concerns related to use in healthy volunteers or if absorption is altered upon multiple dosing. The maximal clinical dose of the investigational drug should be evaluated along with the maximal dose of acid reducing agent in order to best understand the most extreme drug interaction scenario that could occur in clinical practice.

The choice of acid reducing agent includes proton pump inhibitors (PPIs), H₂ blockers and antacids. Proton pump inhibitors take approximatley 4 to 5 days to reach maximal efficacy and due to their mechanism of action the pharmacodynamic effect of increased gastric pH is long lasting and therefore staggering the dose of investigational drug relative to that of the PPI is unlikely to resolve any drug interaction if one does occur. H₂ blockers can maximize pH increases for a much shorter duration after dosing and therefore can potentially be administered with the investigational drug by staggering the dosing sufficiently to avoid a drug interaction. And finally antacids have a short duration of action and therefore it is simplest to mitigate any drug interaction by administering the investigational drug 2 hours prior to or post administration of the antacid. An important consideration to note when selecting the acid reducing agent is to ensure that there are no other potential interactions with metabolism of the investigational drugs.

Data Analysis

The pharmacokinetics of the investigational drug and any active metabolite that contributes towards safety and efficacy should be evaluated thoroughly. The pharmacokinetic (PK) blood samples should be collected in a manner that allows the adequate characterization of PK parameters. In particular, maximal observed concentration (C_max), time of maximal observed concentration (T_max), area under the concentration versus time curve extrapolated to infinity (AUC_0-∞) following single doses, area under the concentration vs time curve over a dosing interval AUC_τ and minimum concentration C_min following multiple doses.

Modeling Approaches

Population based pharmacokinetics can be used to better understand the impact of acid reducing agents on the pharmacokinetics of an investigational drug. However, accurate dosing information of both the investigational drug and acid reducing agent are critical to interpretation of the potential drug interaction. Physiologically based pharmacokinetic modeling is another area of study which is rapidly evolving and could be used to further understanding of potential drug interactions.

Interpretation of Study Results and Clinical Relavence

Findings from one acid reducing agent can be translated within the same class, however, this is not the case between classes. Depending on the particular interacting acid reducing agent the recommendation will vary.

PPI – For PPIs, since the effect is long-lasting, staggering the dose of the investigational drug will not be helpful, therefore administering with a PPI should either be avoided or a lower dose of the PPI could be evaluated further.

H₂ blockers – Since H2 blockers exert their effect for less time than PPIs, the recommendation would be either to avoid use of H₂ blockers or the sponsor could evaluate staggered dosing in a clinical study.

Antacids – In the case of antacids, the dosing recommendation would be either avoid administration of the investigational drug with antacids or stagger dosing by 2 hours, i.e. administration of the investigational drug either 2 hours prior or post administration of the antacid. If a shorter duration is warranted a further clinical study investigating a reduced duration between administration of the investigational drug and antacid should be conducted.

Our Expertise

Study design and selection of pharmacokinetic concentration timepoints to be taken during a clinical study are critical factors to provide meaningful conclusions on the impact of gastric pH on pharmacokinetic drug interactions. Our team has extensive experience with study design, analysis and reporting of drug interactions on pharmacokinetics. If you have any questions regarding your clinical development program and the need to run a dedicated drug interaction study with acid reducing agents do reach out to us.