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Concise recommendations are given regarding the use of allometric and PBPK extrapolation methodologies in the translation process. The results presented here should alert clinical investigators to the limitations inherent in all approaches to prediction of human pharmacokinetics from preclinical data. We propose an adaptive approach to the design of early-phase clinical studies, particularly when dealing with compounds that are characterized by novel and only partially understood pharmacological profiles.

The treatment of organophosphate-induced poisoning is based mainly on atropine and an oxime. Prompt anticonvulsive intervention is usually also required to terminate the ensuing seizure activity and to prevent delayed permanent brain damage. Midazolam, a water-soluble benzodiazepine agonist, has the advantage of rapid absorption following intramuscular administration. In mass casualty situations, the availability of an autoinjector, filled with midazolam, might be a further advantage. In the present study, the plasma pharmacokinetics of midazolam after administration by an autoinjector was compared with conventional intramuscular (i.m.) administration in two groups of four pigs each. During the first 15 min after injection, significantly higher plasma concentrations of midazolam were detected following autoinjector administration, compared with the i.m. injection. The physiological reflection of the accelerated midazolam absorption was a marked reduction in the time interval required for muscle relaxation, induced by midazolam. It is concluded that a midazolam autoinjector might be helpful in the mass casualty scenario following organophosphate poisoning.

The extrapolation from animal data to therapeutic effects in humans, a basic pharmacological issue, is especially critical in studies aimed to estimate the protective efficacy of drugs against nerve agent poisoning. Such efficacy can only be predicted by extrapolation of data from animal studies to humans. In pretreatment therapy against nerve agents, careful dose determination is even more crucial than in antidotal therapy, since excessive doses may lead to adverse effects or performance decrements. The common method of comparing dose per body weight, still used in some studies, may lead to erroneous extrapolation. A different approach is based on the comparison of plasma concentrations at steady state required to obtain a given pharmacodynamic endpoint. In the present study, this approach was applied to predict the prophylactic efficacy of the anticholinergic drug caramiphen in combination with pyridostigmine in man based on animal data. In two species of large animals, dogs and monkeys, similar plasma concentrations of caramiphen (in the range of 60-100 ng/ml) conferred adequate protection against exposure to a lethal-dose of sarin (1.6-1.8 LD(50)). Pharmacokinetic studies at steady state were required to achieve the correlation between caramiphen plasma concentrations and therapeutic effects. Evaluation of total plasma clearance values was instrumental in establishing desirable plasma concentrations and minimizing the number of animals used in the study. Previous data in the literature for plasma levels of caramiphen that do not lead to overt side effects in humans (70-100 ng/ml) enabled extrapolation to expected human protection. The method can be applied to other drugs and other clinical situations, in which human studies are impossible due to ethical considerations. When similar dose response curves are obtained in at least two animal models, the extrapolation to expected therapeutic effects in humans might be considered more reliable.

1311-labeled human serum amyloid P component, which was injected into mice with experimentally induced systemic AA amyloidosis and into controls, became specifically localized and was retained in amyloidotic organs. In comparison, it was rapidly and coimpletely eliminated from unaffected tissues and from control animals. Distinctive images of this amyloidspcecific deposition of labeled serum amyloid P component were derived from whole body scanning, in vivo, of amyioidotic mice. These findings suggest that such im-

Background: Therapeutic drug monitoring (TDM) for busulfan supports dose adjustment during conditioning for stem cell transplantation. The authors aimed to develop and validate limited sampling strategies (LSS) of 4–5 samples for a precise estimation of the area under concentration (AUC)-time curve of busulfan, in plasma as an alternative to an intensive sampling strategy (ISS) requiring 9–10 samples. Methods: ISS TDM data from 297 patients (≤18 years of age) were used. AUCLSS was calculated using the trapezoidal rule and multiple linear regression (MLR). Unlike more complex modeling methods, MLR does not require sophisticated software or advanced training of personnel. MLR coefficients were estimated in the development subset containing randomly selected 50% of the records and were then used to calculate the AUCLSS of the remaining records (the validation subset). The agreement between dose adjustment recommendations (DAR) based on ISS and LSS, in the validation subset, was evaluated by a Bland–Altman analysis. A DAR deviating from an ISS-based reference by <15% was deemed acceptable. Results: Twelve LSSs were acceptable. Sampling at 0, 120, 180, and 240 minutes after the start of the second infusion (LSS15) yielded the best performance, with DAR deviating from the reference by <10% for 95% of cases; the AUCLSS was determined as follows: AUCLSS = 74.7954 × C(0) + 81.8948 × C(120) + 38.1771 × C(180) + 138.1404 × C(240) + 54.1837. This LSS and LSS13 performed similarly well in an independent external validation. Conclusions: MLR-based estimates of AUCLSS provide DARs that deviate minimally from the reference. LSSs allow the reduction of patient discomfort, a ∼50% reduction of TDM-related workload for nursing staff and blood loss and a ∼25% reduction in laboratory workload. These benefits may encourage wider use of busulfan TDM, supporting safe and efficacious personalized dosing.