The aim of the study was to assess the magnitude of the CYP3A4 inhibitory effect of 2 dosing regimens of ketoconazole and the influence of the pharmacokinetic properties of the CYP3A4 substrate on the extent of the substrate exposure increase. For this purpose, a clinical study was conducted and PBPK modeling simulations were performed. A crossover study was conducted in healthy subjects. The study was designed to compare the effects of different regimens of reversible CYP3A4 inhibitors, i.e., ketoconazole 400 mg OD, ketoconazole 200 mg BID, on two CYP3A4 substrates, alprazolam and midazolam, reflecting different pharmacokinetic properties in terms of first-pass effect and elimination. In parallel, time-based simulations were performed using the Simcyp population-based Simulator to address the usefulness of modeling to assess interaction clinical study design with CYP3A4 substrates. Comparison of the OD versus BID regimens for ketoconazole showed an opposite trend for the 2 substrates: BID (200 mg) dosing regimen provided the maximal clearance inhibition for alprazolam, while it was OD (400 mg) dosing regimen for midazolam. However, these effects are moderate despite the well-known pharmacokinetic differences between these substrates, suggesting that these differences are not enough. In the other way round, these investigations show how two CYP3A4 substrates can be different without leading to a major impact of the ketoconazole dosing regimen. The clinical findings are consistent with the Simcyp predictions, in particular the opposite trend observed with midazolam and alprazolam and the ketoconazole dosing regimen. These clinical investigations showed the influence of the CYP3A4 substrates' pharmacokinetic properties and the relevance of ketoconazole dose regimen on the magnitude of the interaction ratios. In addition, PBPK Simcyp simulations demonstrated how they can be used to help clinical study design assessment to capture the maximum effect.
Background Improving the quality of medicines prescribing is one of the first steps to ensuring patient safety in hospital wards. Every day, in the geriatric department of Toulouse University Hospital, pharmacists analyse all new prescriptions. However, in long-term care units treatments are not always re-evaluated and this can lead to inappropriate prescribing or monitoring. Purpose To detect and describe the prescribing errors in four long-term geriatric care units despite daily pharmaceutical analysis. Materials and methods This study was conducted between January and August 2011 in 4 long-term geriatric care units of Toulouse University Hospital. Prescriptions were reviewed by three residents and two pharmacists. All interventions were proposed to three geriatricians for validation, recorded in an Excel spreadsheet and coded according to the criteria defined by the French Society of Clinical Pharmacy. The drug-related problems (=DRPs) and the most frequently involved drug classes were then described. Results We reviewed the treatment of 135 inpatients: 64.4% women and 35.6% men. Mean age was 82.9 years old. We analysed 1492 lines of drugs and detected 471 potential drug-related problems (DRPs) in 125 inpatients. Drugs without indication represented 48% of DRPs, followed by improper administration (e.g. inappropriate route of administration) (18.5%), failure to receive drug (12%) and sub/supratherapeutic dosage (5%). Of all interventions, 298 (63.3%) were accepted and resulted in a modification of the prescription. The classes of drugs most involved in DRPs and pharmaceutical interventions were ‘Nervous system’ drugs (42%) and ‘Alimentary tract and metabolism’ drugs (22%). Conclusions The high number of interventions accepted confirms that prescribing in long-term care units needed to be reviewed, despite daily pharmaceutical analysis. The major types of DRPs encountered, such as drugs without indication, reflect the lack of prescription update regarding the patients’ current condition. This analysis underlines the importance of thoroughly and regularly re-evaluating medicines prescribing in long-term care units of hospital geriatric departments. No conflict of interest.
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