Bioavailability (BA) and Bioequivalence (BE) of Endogenous Substance Drug Products Dale P. Conner,...
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![Page 1: Bioavailability (BA) and Bioequivalence (BE) of Endogenous Substance Drug Products Dale P. Conner, Pharm.D. Division of Bioequivalence OGD, CDER, FDA.](https://reader033.fdocuments.net/reader033/viewer/2022050908/56649d845503460f94a6b33f/html5/thumbnails/1.jpg)
Bioavailability (BA) and Bioequivalence (BE) of
Endogenous Substance Drug Products
Dale P. Conner, Pharm.D.
Division of Bioequivalence
OGD, CDER, FDA
![Page 2: Bioavailability (BA) and Bioequivalence (BE) of Endogenous Substance Drug Products Dale P. Conner, Pharm.D. Division of Bioequivalence OGD, CDER, FDA.](https://reader033.fdocuments.net/reader033/viewer/2022050908/56649d845503460f94a6b33f/html5/thumbnails/2.jpg)
Objective
• Awareness topic discussion
• Provide information to ACPS on the challenges for BA/BE assessment of endogenous drugs
• More detailed discussion is planned for the future– Biopharmaceutics Subcommittee meeting
– ACPS meeting
• At this meeting FDA seeks ACPS recommendations on how to develop the information needed to enhance the science in this area.
![Page 3: Bioavailability (BA) and Bioequivalence (BE) of Endogenous Substance Drug Products Dale P. Conner, Pharm.D. Division of Bioequivalence OGD, CDER, FDA.](https://reader033.fdocuments.net/reader033/viewer/2022050908/56649d845503460f94a6b33f/html5/thumbnails/3.jpg)
Introduction
• BA and BE of endogenous substance drug products need special considerations
• Not addressed in the general BA/BE guidance, “Bioavailability and Bioequivalence Studies for Orally Administered Drug Products - General Considerations”
![Page 4: Bioavailability (BA) and Bioequivalence (BE) of Endogenous Substance Drug Products Dale P. Conner, Pharm.D. Division of Bioequivalence OGD, CDER, FDA.](https://reader033.fdocuments.net/reader033/viewer/2022050908/56649d845503460f94a6b33f/html5/thumbnails/4.jpg)
Introduction
• Specific recommendations– Potassium Chloride Modified-Release Tablets and
Capsules: In Vivo Bioequivalence and In Vitro Dissolution Testing (Draft - Issued 8/2002, Posted 8/6/2002)
– Levothyroxine Sodium Tablets - In Vivo Pharmacokinetic and Bioavailability Studies and In Vitro Dissolution Testing (Issued 2/2001, Posted 3/8/2001)
![Page 5: Bioavailability (BA) and Bioequivalence (BE) of Endogenous Substance Drug Products Dale P. Conner, Pharm.D. Division of Bioequivalence OGD, CDER, FDA.](https://reader033.fdocuments.net/reader033/viewer/2022050908/56649d845503460f94a6b33f/html5/thumbnails/5.jpg)
Introduction
• Other Drugs with no specific BA/BE guidance– Estrogens
– Testosterone
– Progesterone
– Calcitriol
– Ursidiol
– Insulin
– Human growth hormone
![Page 6: Bioavailability (BA) and Bioequivalence (BE) of Endogenous Substance Drug Products Dale P. Conner, Pharm.D. Division of Bioequivalence OGD, CDER, FDA.](https://reader033.fdocuments.net/reader033/viewer/2022050908/56649d845503460f94a6b33f/html5/thumbnails/6.jpg)
Definition of Bioequivalence
• Pharmaceutical equivalents whose rate and extent of absorption are not statistically different when administered to patients or subjects at the same molar dose under similar experimental conditions
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Purpose of BE
• Therapeutic equivalence (TE)
• Bioequivalent products can be substituted for each other without any adjustment in dose or other additional therapeutic monitoring.
• The most efficient method of assuring TE is to assure that the formulations perform in an equivalent manner.
![Page 8: Bioavailability (BA) and Bioequivalence (BE) of Endogenous Substance Drug Products Dale P. Conner, Pharm.D. Division of Bioequivalence OGD, CDER, FDA.](https://reader033.fdocuments.net/reader033/viewer/2022050908/56649d845503460f94a6b33f/html5/thumbnails/8.jpg)
Model of Oral Dosage Form Performance
TherapeuticEffect
Dosage Form
Gut WallDrug in Solution
BloodSite of Activity
Pharmacokinetic MeasurementDosage Form
Performance
Clinical/PD Measurem
ent
ln DoseDose
![Page 9: Bioavailability (BA) and Bioequivalence (BE) of Endogenous Substance Drug Products Dale P. Conner, Pharm.D. Division of Bioequivalence OGD, CDER, FDA.](https://reader033.fdocuments.net/reader033/viewer/2022050908/56649d845503460f94a6b33f/html5/thumbnails/9.jpg)
Model of Oral Dosage Form Endogenous Drug Performance
TherapeuticEffect
Dosage Form
Gut WallDrug in Solution
BloodSite of Activity
Pharmacokinetic MeasurementDosage Form
Performance
Clinical/PD Measurem
ent
ln DoseDose
Body Production Feedback
![Page 10: Bioavailability (BA) and Bioequivalence (BE) of Endogenous Substance Drug Products Dale P. Conner, Pharm.D. Division of Bioequivalence OGD, CDER, FDA.](https://reader033.fdocuments.net/reader033/viewer/2022050908/56649d845503460f94a6b33f/html5/thumbnails/10.jpg)
Model of Oral Dosage Form Endogenous (KCl) Drug Performance
TherapeuticEffect
Dosage Form
Gut WallDrug in Solution
BloodSite of Activity
Pharmacokinetic MeasurementDosage Form
Performance
Clinical/PD Measurem
ent
ln DoseDose
Body Stores
Urine
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Statistical Analysis (Two One-sided Tests Procedure)
• AUC and Cmax
• Log-transformed data
• ANOVA– Model: Period, Sequence, Subject(Seq),
Treatment
• 90% Confidence Intervals (CI) must fit between 80-125%
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Issues with Endogenous Substance
Bioavailability/Bioequivalence
• Assay sensitivity
• Endogenous baseline
• Feedback inhibition of endogenous production
• Circadian rhythm
• Linear/non-linear pharmacokinetics
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Agenda
• Case Study I: Levothyroxine - Background– Results of a Study by Abbott Labs– Levothyroxine BA
• Case Study II: Potassium Chloride
• Summary
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![Page 15: Bioavailability (BA) and Bioequivalence (BE) of Endogenous Substance Drug Products Dale P. Conner, Pharm.D. Division of Bioequivalence OGD, CDER, FDA.](https://reader033.fdocuments.net/reader033/viewer/2022050908/56649d845503460f94a6b33f/html5/thumbnails/15.jpg)
Summary
• BE is a test of the comparative performance of formulations– Release of the drug substance from the drug
product– Rate– Extent
![Page 16: Bioavailability (BA) and Bioequivalence (BE) of Endogenous Substance Drug Products Dale P. Conner, Pharm.D. Division of Bioequivalence OGD, CDER, FDA.](https://reader033.fdocuments.net/reader033/viewer/2022050908/56649d845503460f94a6b33f/html5/thumbnails/16.jpg)
Summary
• Baseline correction of data may be necessary to ensure a sensitive method for the demonstration of BE– Characteristics of baseline– Methods for correction– Magnitude of baseline in relationship to the
values after treatment
![Page 17: Bioavailability (BA) and Bioequivalence (BE) of Endogenous Substance Drug Products Dale P. Conner, Pharm.D. Division of Bioequivalence OGD, CDER, FDA.](https://reader033.fdocuments.net/reader033/viewer/2022050908/56649d845503460f94a6b33f/html5/thumbnails/17.jpg)
Summary
• Endogenous baselines that change due to the administration of exogenous drug substance present a technical challenge to the demonstration of BA and BE– Circadian patterns– Feedback– Pharmacokinetics
![Page 18: Bioavailability (BA) and Bioequivalence (BE) of Endogenous Substance Drug Products Dale P. Conner, Pharm.D. Division of Bioequivalence OGD, CDER, FDA.](https://reader033.fdocuments.net/reader033/viewer/2022050908/56649d845503460f94a6b33f/html5/thumbnails/18.jpg)
Summary
• Can a decision tree be developed that will guide sponsors in the correct BA and BE studies to be done for other endogenous drug products?