Preclinical trials metabolism

Preclinical trials stage II Pharmacokinetics (absorption, distribution, metabolism, and excretion), subchronic toxicity, teratogenicity, mutagenicity, scale-up of synthesis, development of final dosage form, and production of clinical samples [Chemistry, Manufacturing, and Control (CMC) section for FDA],... 

Elvitegravir (18, GS-9137, JTK-303, EVG) is the second IN strand transfer inhibitor to advance into phase III clinical trials (Figure 7). EVG was derived from the quinolone antibiotics which do not show IN activity [39-41]. Through careful optimization, this work resulted in EVG displaying enzyme and antiviral activity of 7.2 and 0.9 nM, respectively. EVG has moderate bioavailability in preclinical species (29 and 34%), low clearance (Qp 0.5 and l.OL/h/kg) and a moderate half-life of 2.3 and 5.2h in rats and dogs, respectively [42]. It is primarily metabolized via CYP450 oxidation and shows a marked increase in human exposure with RTV boosting. 

Droloxifene (3-hydroxy-tamoxifen) behaves as an estrogen agonist in bone tissue and several lipid and coagulation markers in castrated rat models and does not show stimulation of the endometrial epithelium in preclinical studies (Ke et al. 1997). Endometrial stimulation has, however, been observed in clinical trials, which, together with the fact that as an estrogen agonist it is ten times less potent than tamoxifen in bone tissue and lipid metabolism (Hendrix et al. 2001) and that in a recent head-to-head comparison with tamoxifen droloxifene was demonstrated not to be superior in any parameter of breast cancer treatment efficacy (Buzdar et al. 2002), has resulted in cancellation of its clinical development. 

The preclinical stage of drug development focuses on activities necessary for filing an IND/CTA. The completed IND/CTA contains information that details the drug s composition and the synthetic processes used for its production. The IND/CTA also contains animal toxicity data, protocols for early phase clinical trials, and an outline of specific details and plans for evaluation. Process research, formulation, metabolism, and toxicity are the major areas of responsibility in this development stage. Analysis activities that feature LC/MS primarily focus on the identification of impurities, de-gradants, and metabolites. 

Several preclinical studies, originally designed to support the above clinical trials, have been carried out. From these it was determined that m-THPC is not metabolized in vivo and virtually all the drag is eliminated via the liver. Pharmacokinetic data derived from animal studies with m-THPC led to the prediction that this substance would show rapid clearance from plasma in humans. Surprisingly, however, this was only observed in the animal models (dog, rabbit, rat), not in the human populations. This dichotomy stands as a cogent reminder that caution must always be exercised in translating animal-model data into human-dosing decisions [225]. 

In an initial confirmation of the preclinical findings, a phase II clinical trial using 10-40 mg of MDL 100907 per day for 6 weeks showed improved Parkinson rating scale (BPRS) scores relative to placebo and no EPS liability (665). A larger phase III trial showed some minor improvement in positive symptoms at the 10-mg/day dose, but this effect disappeared at the 20-mg/day dose, compared with placebo. Functional PET scans of selected patients in the trial showed minor metabolic changes in the frontal cortex at the 10 but not 20 mg dose. Clinical trials of MDL100907 have been halted, presumably because of limited efficacy (666). Between the findings with ritan-... 

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