Use of an indirect effect model to describe the LDL cholesterol-lowering effect by statins in hypercholesterolaemic patients.

Statins are the most commonly prescribed agents for the treatment of hypercholesterolaemia. This is due to their efficacy in reducing low-density lipoprotein cholesterol (LDL) level which is the primary goal of the treatment especially for patients with multiple risk factors or with established coronary heart diseases. The purpose of this study was to develop a pharmacokinetic/pharmacodynamic (PK/PD) model that describes the LDL-lowering process in patients with hypercholesterolaemia treated with atorvastatin, fluvastatin or simvastatin. A total of 100 patients were studied retrospectively. They received atorvastatin (n = 57), fluvastatin (n = 26) or simvastatin (n = 17). As no pharmacokinetic data were available, the absorption rate was fixed to 1/h and atorvastatin, simvastatin and fluvastatin elimination half-lives were fixed to 14, 2 and 2.5 h respectively. A total of 309 LDL levels were measured and the data were analysed by nonmem v. The time course of the LDL-lowering effect of statins was described by an indirect-response model with precursor (LDL synthesis, input rate K(in)) and response (circulating LDL, input and output rates K) compartments. The following parameters were estimated: LDL input rate (K(in)) 0.14 +/- 0.015 g/L/day (mean +/- SD); inhibition fraction of K(in) (INH) 0.21 +/- 0.017; and dose producing 50% increase of LDL removal (D50), 26 +/- 7.8, 1.3 +/- 0.48 and 15 +/- 5.25 mg for atorvastatin, simvastatin and fluvastatin, respectively. Gender, bodyweight, age, calories/day, sugar/day, lipids/day, hyperlipidaemia types and waist/hip circumference, renal and hepatic functions had no effect on the pharmacodynamic parameters. The pharmacodynamic parameters for the three statins were accurately estimated. The PK/PD model developed successfully predicted the time course of the LDL-lowering effect of statins.

[The EMEA CHMP guidelines in coronary heart disease and chronic heart failure]. / Les recommandations du Comite des Spécialités Pharmaceutiques de l'Agence Européenne du Me'dicament dans la maladie coronaire et l'insuffisance cardiaque chronique.

The official regulatory recommendations for drug development and the granting of marketing authorisations are intended for use by pharmaceutical companies and the regulatory agencies. These recommendations are particularly useful in Europe, and allow harmonisation of the regulatory requirements between the different member states, thus facilitating further evaluation of the submission file and the registration process. The European guidelines are issued by the Committee for Human Medicinal Products (CHMP) of the European Agency for the Evaluation of Pharmaceutical Products (EMEA). The key points of the current guidelines regarding applications for phase III trials in coronary heart disease (stable angina, acute coronary syndromes) and chronic heart failure are presented. They are as follows: the definition of selected populations, the choice of criteria for evaluating efficacy and safety, the choice of comparators, and study duration etc.

Methodology for the evaluation of drugs in pregnant women.

Although drugs are prescribed during pregnancy with some reluctance, they fulfill a real need in some circumstances. Adequate drug evaluation is thus essential, either based on efficacy and safety or mainly safety, using available data from non-pregnant women. Evaluation methodology is not fundamentally different during pregnancy. Recommendations for drug development are formulated on the basis of the most common situations as well as specific suggestions, thus raising the awareness of the different partners participating in healthcare (institutions, the pharmaceutical industry and prescribers). In particular, regulatory and economic incentives superimposed upon those recommendations adopted in Europe and the US for orphan diseases should be put into place to assist in the evaluation of drugs used in obstetrics. Medical needs in obstetrics should be better identified, and labelling of drugs for use during pregnancy should be better directed towards prescribers; a national registry of pregnancies should be established in France.

A comprehensive description of muscle symptoms associated with lipid-lowering drugs.

UNLABELLED: A spectrum of disease from myalgia to rhabdomyolysis exists as classic side-effect of lipid-lowering treatment (LLT). While myopathy has generated considerable interest, mild musculo-skeletal symptoms are poorly assessed. OBJECTIVE: To report on the muscular side-effects of LLT with a particular focus on the overlooked milder ones. METHODS: Hyperlipidemic patients under LLT and complaining of muscle symptoms were asked to complete a self administered questionnaire. Among the 815 adult hyperlipidemic patients under LLT and referred to the cardiovascular prevention unit of La Pitie Hospital, 165 patients answered that they experienced, or had experienced, muscle symptoms which they attributed to the LLT. One hundred and thirty three of these completed and returned a self-administered questionnaire. RESULTS: A clear chronological link between symptoms and the LLT was revealed, either because they appeared soon after drug initiation or because of an improvement after drug withdrawal. While cramps and stiffness were the most frequent symptoms, tendonitis-associated pain was surprisingly common, reported in almost half the cases. Pain was often diffuse with a focus on a given location, mainly lower limbs. 39% of patients had used analgesics for pain relief. Unpredictably, a majority of patients reported pain during rest and the lying position. In a number of cases, a family history of pain under LLT was revealed. CONCLUSION: The impact of these mild symptoms on daily activities might not be negligible in a subset of patients. The role and importance of a genetic background predisposing to low-grade myopathy deserves further investigation.