Evaluating the Clinical Impact of Formulation Variability: A Metoprolol Extended‐Release Case Study

Abstract

The objective of this research was to evaluate the impact of changes in the formulation of metoprolol extended‐release (ER) tablets on dissolution, pharmacokinetic, and exercise‐induced heart rate (EIHR) using a combined physiologically based absorption pharmacokinetic, and population pharmacokinetic/pharmacodynamic modeling and simulation approach. Using a previously developed physiologically based absorption pharmacokinetic model in DDDPlus and GastroPlus, we simulated the changes in drug release and exposure as the result of quantitative changes in the release‐controlling excipient, hydroxylpropylmethylcellulose, for 50 and 200 mg. The similarity of dissolution profiles was assessed using the f2 test, and bioequivalence was tested on the simulated pharmacokinetic profiles. We used the simulated concentration‐time profiles following formulation changes as pharmacokinetic input into a population pharmacokinetic/pharmacodynamic model newly developed in NONMEM to determine if changes in pharmacokinetics lead to clinically significant changes in pharmacodynamics. Pharmacodynamic assessment was based on the percentage reduction in the EIHR from baseline. Therapeutic effect was considered similar when the model‐predicted EIHR was within 50% to 85% of the average maximum EIHR of healthy 30‐year‐old subjects. A 40% or more increase in the release rate constant resulted in dissimilarity in dissolution profiles and bioINequivalence in pharmacokinetics for both 50 and 200 mg. Formulation‐related differences in drug release of metoprolol ER tablets can lead to differences in pharmacokinetics. However, the evaluated pharmacokinetic differences do not lead to clinically meaningful differences in EIHR, suggesting that EIHR may not be sensitive enough to detect changes in pharmacokinetics of metoprolol ER products.

In Vitro Dissolution and in Silico Modeling Shortcuts in Bioequivalence Testing

“…Formulation changes were made through altering in vivo dissolution, which indicates that the platform can be subject to optimization by the operator. In another study, the simulated concentration-time profiles following formulation changes obtained by GastroPlus™ were used as pharmacokinetic input into NONMEM ® to determine if pharmacokinetics changes would affect the metoprolol pharmacodynamics significantly [62]. However, it was found that no significant therapeutic effect differences were produced despite pharmacokinetic changes, but this was attributed to the insensitivity of the endpoint used.…”

Pharmacometrics, Physiologically Based Pharmacokinetics, Quantitative Systems Pharmacology—What's Next?—Joining Mechanistic and Epidemiological Approaches

“…The hypothesis generated by the pharmacoepidemiologic approach was then evaluated by integrated physiologically‐based absorption and population pharmacokinetic/pharmacodynamic models to evaluate the biological, physiological, and drug‐related and/or formulation‐related causes of the observed reduced efficacy or adverse event–drug pair report. Physiologically‐based absorption modeling coupled with population pharmacokinetic/pharmacodynamic modeling can be used to investigate if realistic changes in pharmaceutical variables (e.g., variables affecting dissolution rate, intestinal motility, or primary and secondary active transport across the intestinal membrane) may result in the observed purported reduced efficacy or adverse events arising from generic substitution . This strategy was applied retrospectively to a historic case example of extended‐release metoprolol as well as to antiepileptic drugs to establish the scientific approach ( Figure ) followed by a prospective application to direct acting oral anticoagulants to rank order the anticipated bleeding risk associated with soon‐to‐be marketed generic dabigatran, edoxaban, rivaroxaban, and apixaban.…”

“…Rather, perpetrators that are highly prevalent but perhaps with weaker drug–drug interaction profiles may be prioritized as they represent an overall larger absolute impact. Likewise, the extension of pharmacokinetic/pharmacodynamic and physiologically‐based pharmacokinetic models must consider the measurement of relevant population‐level clinical outcomes rather than more discrete pharmacological changes that are not captured in these databases, e.g., increased rate of heart attacks vs. increased heart rate variability . By using a combined approach, the strength of evidence is greatly increased and elevates its impact on regulatory and clinical decision‐making with much greater certainty.…”

“…intestinal motility, or primary and secondary active transport across the intestinal membrane) may result in the observed purported reduced efficacy or adverse events arising from generic substitution. 7,8 This strategy was applied retrospectively to a historic case example of extended-release metoprolol as well as to antiepileptic drugs to establish the scientific approach (Figure 1) followed by a prospective application to direct acting oral anticoagulants to rank order the anticipated bleeding risk associated with soon-to-be marketed generic dabigatran, edoxaban, rivaroxaban, and apixaban.…”

Physiologically‐based pharmacokinetics modeling to investigate formulation factors influencing the generic substitution of dabigatran etexilate

“…To this end, we selected four representatives of DOACs: DABE, apixaban, rivaroxaban, and edoxaban to quantitively predict the impact of change in active pharmaceutical ingredient particle properties of these products on both BE and clinical outcomes using our previously demonstrated PBPK-population PK (Pop-PK)-pharmacodynamic (PD) approach. 18,19 Among the DOACs, DABE has a bioavailability of 3%-7%. It is consequently more likely to be affected by formulation design differences.…”