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ADVISORY COMMITTEE FOR PHARMACEUTICAL SCIENCE

ADVISORY COMMITTEE FOR PHARMACEUTICAL SCIENCE. Drug Transfer into Breast Milk: Nonclinical and Clinical Methods. July 20, 2001. Introduction and Background: Larry Lesko, Ph.D. Draft Lactation Studies Guidance and Questions: Arzu Selen, Ph.D.

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ADVISORY COMMITTEE FOR PHARMACEUTICAL SCIENCE

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  1. ADVISORY COMMITTEE FOR PHARMACEUTICAL SCIENCE Drug Transfer into Breast Milk: Nonclinical and Clinical Methods July 20, 2001

  2. Introduction and Background: • Larry Lesko, Ph.D. • Draft Lactation Studies Guidance and Questions: Arzu Selen, Ph.D. • Nonclinical and Clinical Methods to Determine the Amount of Drug in Breast Milk: Advantages and Areas • for Improvement: Shinya Ito, M.D. and • Pat McNamara, Ph.D. • Questions and Panel Discussion Outline of the Session:

  3. Draft Lactation Studies (Drug Transfer into Breast Milk)Guidance Arzu Selen, Ph.D. FDA/CDER/OPS/OCPB/DPE III for the Lactation Studies Working Group July 20, 2001

  4. Lactation Studies Guidance Working Group: Chair: Arzu Selen Dee Kennedy Jurgen Von Bredow Kathleen Uhl Pam Chamberlain Holli Hamilton Margaret Bash Charles Bonapace Anita O'Connor Jen DiGiacinto Peggy Miller Jerry Fetterly Bill Rodriguez John Hunt Jooran Kim Alfredo Sancho Sandra Suarez

  5. Title of the Draft Guidance:Clinical and Non-clinical Studies on the Transfer of Drugs and Biological products into Breast Milk Driving Force

  6. Objectives of the Draft Guidance: • Provide information on the amount of drug (and its significant metabolites) in breast milk as a percentage of • the maternal dose or • the approved infant dose (if available) • Provide clinically meaningful dosing recommendation for the women who would be breast-feeding .

  7. In vitro methods, e.g. mammary cell cultures, equilibrium dialysis

  8. Focus this morning: • Committee and panel’s view on: • the usefulness of measuring drug (and/or its significant metabolite) in breast milk • the reliability of methods used for determining the amount of drug in breast milk

  9. Factors influencing drug exposure in infants: • Transfer and sojourn of drug in milk (mammary drug pharmacokinetics) • Maternal drug pharmacokinetics • Infant drug pharmacokinetics

  10. Drug transfer into breast milk: Facilitated Diffusion Active Transport Diffusion (model for further consideration: log-transformed phase distribution model)

  11. Parameters needed to calculate M/P values using the Log-transformed phase distribution model: • pKa, • log P, • protein binding • H.C. Atkinson and E.J. Begg, Clin. Pharmacokinet., 18, 151-167, 1990.

  12. Using M/P (milk/plasma ratios): • Amount of drug in breast milk • = maternal Cavg x [M/P] x milk intake • Exposure Index • = [milk intake x (M/P)]/Cl infant • S. Ito and G. Koren, Br.J. Clin. Pharmacol., 38, • 99-102, 1994. • where milk intake = 150 ml/kg/day or • = 0.1 ml/kg/min

  13. Questions for Panel Discussion: 1. Is it important to estimate and/or to determine the amount of drug (and/or its significant metabolites) in breast milk? a) For what type of drugs, is information on the extent of drug transfer into breast milk needed?

  14. Questions (Continued): • 1. b)When such information is needed, when is it appropriate to estimate or collect the data from non-clinical (such as animal studies, in vitro studies) and/or clinical studies? • c) What parameters can be used to assess the safety risk presented to breastfed infants by drugs predicted to or demonstrated to transfer into breast milk?

  15. Questions (Continued): 2. For drugs that are primarily transferred into milk by diffusion, equations (such as log phase distribution model) incorporating drug characteristics (such as pKa, Log P, protein binding) and distribution of drug in milk lipids, are shown to be predictive of drug milk to plasma (M/P) ratios. The M/P values are ultimately used to predict the amount of drug in breast milk.

  16. Questions (Continued): 2. a) Would the Panel find utilization of a model such as log phase distribution model acceptable as a first estimate for predicting the extent of drug transfer into milk for all drugs? b) What percent of drugs, an approximation, are transferred into breast milk by processes other than diffusion? c) What can be considered as reliable screen(s) to identify the potential of a drug to be actively transported into milk?

  17. Questions (Continued): 3.The approach followed in calculation of M/P values such as utilizing Area Under Curve (AUC) ratios versus single point ratios can influence the accuracy of this estimate. The accuracy of M/P value is important as this value is further utilized to calculate the amount of drug in breast milk. • a)What are the advantages and limitations of using M/P values (calculated based on AUC ratios) to estimate the extent of drug transferred into breast milk?

  18. Questions (Continued): • b) Are there other acceptable approaches/methods for determining the extent of drug transferred into milk? Would milk drug concentration data alone (instead of both milk and plasma drug concentration data) be satisfactory to determine the extent of drug transferred into milk?

  19. Non-clinical and Clinical Methods • to Assess Drug Transfer into Breast Milk: Advantages and Areas for Improvement • Shinya Ito, M.D. • Pat McNamara, Ph.D.

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