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J Pharm Sci. 2019 Mar 11. pii: S0022-3549(19)30146-7. doi: 10.1016/j.xphs.2019.02.027. [Epub ahead of print]

A novel pharmacokinetic bridging strategy to support a change in the route of administration for biologics.

Author information

1
Division of Clinical Pharmacology II, Office of Clinical Pharmacology, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USA.
2
Division of Pulmonary, Allergy, and Rheumatology Products, Office of Drug Evaluation II, Office of New Drug, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USA.
3
Division of Pharmacometrics, Office of Clinical Pharmacology, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USA.
4
Division of Clinical Pharmacology II, Office of Clinical Pharmacology, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USA. Electronic address: Chandrahas.Sahajwalla@fda.hhs.gov.

Abstract

Determination of appropriate pharmacokinetic endpoint to bridge different dosing regimens is often a challenge when developing a new route of administration for therapeutic proteins. Trough concentrations (Ctrough) is often considered the most relevant PK endpoint to predict efficacy (ACR20/DAS28) in the treatment of rheumatoid arthritis for biologics. However, no systematic research has been conducted to evaluate this approach. We developed a novel strategy to predict the most relevant PK variables that may be used to support a change in the route of administration for biologic products. Our analysis indicated that matching only Ctrough when switching from intravenous dosing to subcutaneous dosing with decreasing dosing interval may result in a lower treatment response. If only average concentration (Cave) is considered as the relevant variable, our analysis showed that treatment response may be worsened when switching from subcutaneous dosing to intravenous dosing with increasing dosing interval. The study results demonstrated that matching a single pharmacokinetic endpoint (Ctrough or Cave) may be not sufficient to ensure efficacy when switching between intravenous dosing and subcutaneous dosing. A practical novel pharmacokinetic bridging approach is provided when switching from subcutaneous to intravenous dosing or switching from intravenous dosing to subcutaneous dosing for biologic products.

KEYWORDS:

Average Concentration; Dosing Interval; Indirect Response Model (IRM); Modeling and simulation; Trough Concentration; rheumatoid arthritis

PMID:
30871994
DOI:
10.1016/j.xphs.2019.02.027

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