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I understand that the FDA is a lot more willing to accept simulations in lieu of clinical studies these days. We are investigating a drug on which we have extensive clinical data. The drug is given by IV infusion and is cleared almost entirely by the kidneys. We have data in normal healthy volunteers as well as in patients. In addition, we also have PK and safety data in subjects with mild and moderate renal impairment. We are thinking of conducting a clinical study in volunteers with severe renal impairment and it looks like these volunteers are not easy to enroll. Can we use modeling and simulation based on the data we have thus far to predict and therefore alter dosing regimen in subjects with severe renal disease? Your thoughts and comments are appreciated.
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I agree with your reasoning, and I think the time is ripe for a thorough
discussion of this topic. These severely impaired volunteers, what are they
really adding to the knowledge base that modelling could not determine? And
furthermore, are these studies even ethical?
Joachim Grevel, PhD
BAST Inc Limited
Nottingham, NG1 1GF
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As Joachim mentioned this is a good topic for discussion and this is an =
area that M&S can help. It seems regulators are receiving more of M&S =
submissions and in some cases they are accepting them as replacement of =
clinical studies, please see the following report:
Zhao P, Zhang L, Grillo JA, Liu Q, Bullock JM, Moon YJ, Song P, Brar SS, =
Madabushi R, Wu TC, Booth BP, Rahman NA, Reynolds KS, Berglund EG, Lesko =
LJ and Huang SM (2011) Applications of Physiologically Based =
Pharmacokinetic (PBPK) Modeling and Simulation During Regulatory Review. =
Clin Pharmacol Ther 89:259-267 =
There are also attempts to model the disease status and simulate the PK =
changes using PBPK models with a good degree of success, please see:
Edginton AN and Willmann S (2008) Physiology-Based Simulations of a =
Pathological Condition: Prediction of Pharmacokinetics in Patients with =
Liver Cirrhosis. Clinical Pharmacokinetics 47:743-752.
Johnson TN, Boussery K, Rowland-Yeo K, Tucker GT and Rostami-Hodjegan A =
(2010) A Semi-Mechanistic Model to Predict the Effects of Liver =
Cirrhosis on Drug Clearance. Clinical Pharmacokinetics 49:189-206.
Strougo A, Yassen A, Krauwinkel W, Danhof M and Freijer J (2011) A =
semi-physiological population model for prediction of the =
pharmacokinetics of drugs under liver and renal disease conditions. Drug =
Metabolism and Disposition.
Rowland Yeo K, Aarabi M, Jamei M and Rostami-Hodjegan A (2011) Modeling =
and predicting drug pharmacokinetics in patients with renal impairment. =
Expert Review of Clinical Pharmacology 4:261-274.
Obviously, the level of success in such exercises, among other things, =
heavily depends upon the available knowledge of underlying =
physiological/biological changes over the disease course.
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