Pharmacokinetic trials

While the numbers of animals involved in research is tracked closely and is well known, such is not the case for human subjects involved in clinical trials. We simply do not know how many are involved in such trials in the United States, much less worldwide. Though the NIH does track closely how many dollars and individuals are involved in research it funds ( 12.7 billion and seven million subjects in 1997), the same is not true for privately funded research (where the numbers are greater). And while there is now a Web site where one can examine the numbers and types of efficacy trials open, the same is not true for Phase I tolerance and pharmacokinetic trials, where most potential drugs cease development. 

Phase I. Initial safety trials on a new medicine, usually conducted in normal male volunteers. An attempt is made to establish the dose range tolerated by volunteers for single and for multiple doses. Phase I trials are sometimes conducted in severely ill patients (e.g., in the field of cancer) or in less ill patients when pharmacokinetic issues are addressed (e.g., metabolism of a new antiepileptic medicine in stable epileptic patients whose microsomal liver enzymes have been induced by other antiepileptic medicines). Pharmacokinetic trials are usually considered Phase I trials regardless of when they are conducted during a medicine s development. 

Drengler RL, Kuhn JG, Schaaf LJ, et al. Phase I and pharmacokinetic trial of oral irinotecan administered daily for 5 days every 3 weeks in patients with solid tumors. J Clin Oncol 1999 17(2) 685-696. 

Magnus RD, Findling R, Preskorn SH, et al. An open-label pharmacokinetic trial of nefazodone in depressed children and adolescents [Abstract], Psychopharmacol Bull 1997 33 550. 

Aebi, S., et al. 1999. A phase II/pharmacokinetic trial of high-dose progesterone in combination with paclitaxel. Cancer Chemother Pharmacol 44 259. 

Lee EJ, Egorin MJ, Van Echo DA, Cohen AE, Tait N, Schiffer CA. Phase I and pharmacokinetic trial of carboplatin in refractory adult leukemia. J Natl Cancer Inst 1988 80(2) 131-5. 

Thomas J, Tutsch K, Arzoomanian R, Alberti D, Simon K, et al. 1998. Phase I clinical and pharmacokinetic trial of the cyclin-dependent kinase (CDK) inhibitor flavopiridol. Proc. Am. Soc. Clin. Oncol. 17 804 (Abstr.)... 

Venook AP, Egorin MJ, Rosner GL, et al. Phase I and pharmacokinetic trial of gemcitabine in patients with hepatic or renal dysfunction cancer and leukemia group B 9565. J Chn Oncol 2000 18 2780-2787. 

Investigational Formulations. Provide the quantitative composition and lot number of each finished dosage form used in each clinical trial, bioavailability and pharmacokinetic trial, clinical pharmacology trial, and dose tolerance trial conducted during the... 

In the third section, a list of all formulations used in clinical trials and in vivo bioavailability/pharmacokinetic trials together with the trials in which each formulation was used should be provided. For batches used in bioavailability/pharmacokinetic trials, significant manufacturing and formulation changes for the drug product over the course of its evaluation should be identified. 

In this section, the pharmacokinetics for systemic dosage forms should be described, including absorption, routes of excretion, protein binding, metabolic changes to compounds of lesser or greater activity, and distribution into various pharmacokinetic compartments. References to the locations in the NDA of the full reports of the pharmacokinetics trials should be provided. 

Yacyshyn B R, Barish C, et al. (2002). Dose ranging pharmacokinetic trial of high-dose alicaforsen (intercellular adhesion molecule-1 antisense oligodeoxynucleotide) (ISIS 2302) in active Crohn s disease. Aliment. Pharmacol. Ther. 16 1761-1770. 

The classic pharmacokinetic trial is carried out in healthy volunteers with frequent blood sample taken at predetermined times. This sort of study gives high-quality data suitable for good basic modelling. It is also usually relatively easy to estimate parameters... 

Danauser-Reidl S, Hausmann E, Schick H, Bender R, Dietzfelbinger H, Rastetter J, Hanauske A-R. Phase-I clinical and pharmacokinetic trial of dextran conjugated doxorubicin (AD-70, DOX-OXD). Invest New Drugs 1993 11 187-195. 

Rameis H. The importance of prospective planning of pharmacokinetic trials. Considerations of studies on the phenytoin-digoxin-(P-D) and phenytoin-digitoxin-(P-DT) interaction. IntJ Clin Pharmacol Ther Toxicol 992) 30,528-9. 

Svendsen KD, Choi L, Chen B-L, Karolchyk MA. Single-center, open-label, multiple-dose pharmacokinetic trial investigating die effect of rufinamide administration on Ortho-Novum 1/35 in healdiy women. Epilepsia (1998) 39 (Suppl 6), 59. 

No human clinical and pharmacokinetics trials have been performed with this photosensitizer pending the results of the preclinical investigations proposed. 

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