Establishing in vitro to clinical correlations in the evaluation of cardiovascular safety pharmacology.

Preclinical studies are vital in establishing the efficacy and safety of a new chemical entity (NCE) in humans. To deliver meaningful information, experiments have to be well defined and provide outcome that is relevant and translatable to humans. This review briefly surveys the various preclinical experiments that are frequently conducted to assess drug effects on cardiac conductivity in early drug development. We examine the different approaches used to establish correlations between non-clinical and clinical settings and discuss their value in the evaluation of cardiovascular risk.

The in vitro and in vivo evaluation of new synthesized prodrugs of 5-OH-DPAT for iontophoretic delivery.

The feasibility of transdermal iontophoretic transport of 4 novel ester prodrugs of 5-OH-DPAT (glycine-, proline-, valine- and beta-alanine-5-OH-DPAT) was investigated in vitro and in vivo. Based on the chemical stability of the prodrugs, the best candidates were selected for in vitro transport studies across human skin. The pharmacokinetics and pharmacodynamic effects of the prodrug with highest transport efficiency, were investigated in a rat model. The in vitro transport, plasma profile and pharmacological response were analyzed with compartmental modeling. Valine- and beta-alanine-5-OH-DPAT were acceptably stable in the donor phase and showed a 4-fold and 14-fold increase in solubility compared to 5-OH-DPAT. Compared to 5-OH-DPAT, valine- and beta-alanine-5-OH-DPAT were transported less and more efficiently across human skin, respectively. Despite a higher in vitro transport, lower plasma concentration was observed following 1.5h current application (250 microAcm(2)) of beta-alanine-S-5-OH-DPAT in comparison to S-5-OH-DPAT. However the prodrug showed higher plasma concentrations post-iontophoresis, explained by a delayed release due to hydrolysis and skin depot formation. This resulted in a pharmacological effect with the same maximum as 5-OH-DPAT, but the effect lasted for a longer time. The current findings suggest that beta-alanine-5-OH-DPAT is a promising prodrug, with a good balance between stability, transport efficiency and enzymatic conversion.

Analysis of the relationship between age and treatment response in migraine.

In migraine, headache severity varies with age. As a consequence, the effectiveness of medication may also depend on a patient's age. The purpose of this study was to assess the combined effect of age and drug treatment on headache characteristics. Using data from clinical trials of sumatriptan in adolescents and adults, we show how the interaction between age and drug exposure can be parameterised as a covariate on a Markov model that describes the decline of headache severity over three clinically defined stages (no relief, relief and pain-free status). The model explains important clinical observations: (i) the rates at which the pain relief and pain-free status were attained were found to be inversely related to age; (ii) in placebo-treated patients, the mean transit time from 'no relief' to 'relief' is 3 h for young adolescents and increases to 6 h for patients aged >or= 30 years; and (iii) sumatriptan reduces the transit time to 2 h, irrespective of age. These findings indicate that the therapeutic gain over placebo increases with age. Prospective studies of antimigraine drugs should take this relationship into account when extrapolating efficacy data from adults to adolescents.

Prediction of headache response in migraine treatment.

Triptans are efficacious for the acute treatment of migraine attacks. Yet, defining a concentration-effect relation for these compounds is difficult as the dynamics of the migraine attack are not thoroughly understood. The objective of this investigation was to develop a disease model to predict measures of headache in randomized placebo-controlled clinical trials investigating oral sumatriptan as a paradigm compound. A hidden Markov model based on the states of response (no relief, relief, and pain free) and headache scores (observed variable) was used in conjunction with population pharmacokinetics. Model parameters were capable of predicting the course of headache relief, pain-free status and headache recurrence. It was shown that sumatriptan shortens mean transit times between states by up to 5 h. The potency of sumatriptan (EC(50)) was 9 ng/ml. These findings demonstrate the value of combining pharmacokinetic and efficacy information to model disease and characterize time-independent drug properties in a population of migraineurs.

Pharmacokinetic-pharmacodynamic correlations and biomarkers in the development of COX-2 inhibitors.

The mechanism by which COX inhibitors exert their analgesic effect is well established. However, data show no direct correlation between drug concentrations in plasma and the analgesic or adverse effects in chronic inflammatory conditions. This represents a major problem in the development of COX inhibitors, since it is difficult to predict the appropriate dosing regimen for the treatment of chronic inflammatory pain, based upon information from pre-clinical studies and eventually early clinical studies. The factors that determine response in inflammatory pain must be understood in order to make predictions about the time course of the analgesic effect. In this review the determinants of drug response and their variability will be discussed: physicochemical properties, pharmacokinetics (PK), pathophysiology and disease progression. From a mechanistic point of view, endogenous mediators of inflammation might be used as a biomarker for the analgesic effect and safety assessment. Such a biomarker can be an intermediate step between drug exposure and response. In addition, its concentration-effect relationship could be characterized by pharmacokinetic-pharmacodynamic (PK/PD) modelling. Indeed, recent investigations have shown that COX-2 inhibition, as determined by modelling of prostaglandin E2 (PGE2) levels in the whole blood assay in vitro can be used as a marker to predict drug effects (analgesia) in humans. A model-derived parameter, IC80, (total and unbound) was found to correlate directly with the analgesic plasma concentration of different COX inhibitors varying in enzyme selectivity. These findings indicate that PGE2 and thromboxane B2 inhibition can be used to predict and select efficacious doses in humans.