Pharmacokinetics and Pharmacodynamics of Lomitapide in Japanese Subjects.

AIMS: Lomitapide is a licensed treatment for patients with homozygous familial hypercholesterolaemia in the USA, the EU, Canada, and Mexico. This study was conducted to compare the pharmacokinetics (PK), pharmacodynamics, safety, and tolerability of lomitapide between Japanese and Caucasian subjects with elevated low-density lipoprotein cholesterol (LDL-C) after single and multiple doses. METHODS: In this randomized, double-blind, placebo-controlled study, 36 Japanese and 36 Caucasian subjects with LDL-C levels ≥110 mg/dL were administered an escalating lomitapide dose range of 10-60 mg or placebo. Subjects were assessed for safety, tolerability, and lipid levels. RESULTS: Exposure to lomitapide as measured by Cmax was linear and increased over the dose range of 10-60 mg for both single- and multiple-dose administration. The correlation between AUC0-t and Ctrough demonstrated the lack of differences in the PK of lomitapide among ethnic groups. Lomitapide dose-dependent reductions in lipid parameters were observed and showed no ethnic differences. The safety assessments showed that the main treatment-related side effects identified were increases in hepatic enzymes and that the majority of treatment-related treatment-emergent AEs were gastrointestinal disorders. CONCLUSIONS: Lomitapide was effective in reducing LDL-C levels in a dose-dependent manner. Similar PK, efficacy, and safety profiles were observed in Japanese and Caucasian subjects, which suggest no differences in lomitapide activity or metabolism between the two populations compared in this study.

Cancer mortality amongst people with epilepsy: a study of two cohorts with severe and presumed milder epilepsy.

BACKGROUND: People with epilepsy may experience an altered pattern of mortality due to cancer. We determined cancer mortality in two distinct populations with epilepsy: (i) an institutionalised cohort with severe epilepsy (SEC) and (ii) another cohort with presumed milder epilepsy (MEC). METHODS: Mortality data from 1977 until 2003 were obtained for the two cohorts (SEC, n=1358 and MEC, n=4494). Standardised mortality ratios (SMRs) for all causes, all cancers and specific cancer sites were calculated. FINDINGS: The SMR for all cancers was significantly elevated in the SEC (SMR: 1.42; 95%CI: 1.18-1.69) but not in the MEC (SMR: 0.93; 95%CI: 0.84-1.03). The SMR for brain and CNS neoplasms was significantly elevated in the MEC; most cancer deaths in younger ages (<45 years) in this cohort were due to brain and CNS neoplasms. There was also a deficit in deaths due to lung cancer (SMR: 0.68; 95%CI: 0.54-0.84) in this cohort. In the SEC, SMRs for oesophageal (SMR: 2.81, 95%CI: 1.35-5.17), liver (SMR: 4.12, 95%CI: 1.12-10.56) and gall bladder (SMR: 7.32, 95%CI: 1.51-21.38) cancers and non-Hodgkin's lymphoma (SMR: 2.67, 95%CI: 0.98-5.80) were elevated. CONCLUSIONS: The modest excess of all cancer deaths and large excesses of deaths due to cancers at certain sites in the SEC and the lack thereof in the MEC suggests dissimilarity in the risk factor profile of the two populations. These risk factors, whether life style attributes or antiepileptic drugs, need to be identified.