Breaking the chains of lipoprotein lipase deficiency: A pediatric perspective on the efficacy and safety of Volanesorsen.

RATIONALE: Lipoprotein lipase (LPL) deficiency, a rare inherited metabolic disorder, is characterized by high triglyceride (TG) levels and life-threatening acute pancreatitis. Current treatment for pediatric patients involves a lifelong severely fat-restricted diet, posing adherence challenges. Volanesorsen, an EMA-approved RNA therapy for adults, effectively reduces TG levels by decreasing the production of apolipoprotein C-III. This 96-week observational open-label study explores Volanesorsen's safety and efficacy in a 13-year-old female with LPL deficiency. METHODS: The patient, with a history of severe TG elevations, 53 hospital admissions, and life-threatening recurrent pancreatitis despite dietary restrictions, received weekly subcutaneous Volanesorsen injections. We designed a protocol for this investigator-initiated study, primarily focusing on changes in fasting TG levels and hospital admissions. RESULTS: While the injections caused occasional pain and swelling, no other adverse events were observed. TG levels decreased during treatment, with more measurements below the pancreatitis risk threshold compared to pre-treatment. No hospital admissions occurred in the initial 14 months of treatment, contrasting with 21 admissions in the 96 weeks before. In the past 10 months, two pancreatitis episodes may have been linked to dietary noncompliance. Dietary restrictions were relaxed, increasing fat intake by 65% compared to baseline. While not fully reflected in the PedsQL, both parents and the patient narratively reported an improved quality of life. CONCLUSION: This study demonstrates, for the first time, that Volanesorsen is tolerated in a pediatric patient with severe LPL deficiency and effectively lowers TG levels, preventing life-threatening complications. This warrants consideration for expanded access in this population.

CYP1A2 activity is an important determinant of clozapine dosage in schizophrenic patients.

Clozapine is an effective atypical antipsychotic drug applied in the treatment of resistant schizophrenia. The drug is mainly metabolized by cytochrome P-450 (CYP) enzymes especially the isozyme CYP1A2. Remarkably, the effective dosage varies widely among patients, making it necessary to individualize drug therapy with clozapine. The explanation for dosage variation may be differences in drug metabolism, and more specifically of CYP1A2 activity. This study is aimed at determining to what extent variability in clozapine dose can be explained by pharmacokinetic (PK) factors and more specifically by CYP1A2 activity in effectively treated psychiatric patients. In 22 evaluable patients with a schizophrenic disorder chronically using clozapine, the CYP1A2 activity and the clozapine clearance were estimated. For calculation of the pharmacokinetic parameters of clozapine, population PK software based upon Bayesian analysis was used. Caffeine clearance was estimated with the paraxanthine/caffeine ratio and served as estimate of CYP1A2 activity.A significant linear relationship was found between the clozapine dose and clozapine clearance (R: 0.71; P<0.05), whereas no relationship was found between clozapine dosage and clozapine serum trough concentration. Moreover, individual caffeine and clozapine clearances were found to be significantly related (R: 0.62; P<0.05) as were clozapine dose per kg body weight and P/C mol ratio (R: 0.44; P<0.05). We conclude that CYP1A2 activity is an important determinant of the variability of effective clozapine doses in psychiatric patients.

Two novel methods for the determination of CYP1A2 activity using the paraxanthine/caffeine ratio.

Cytochrome P450 1A2 (CYP1A2) plays an important role in drug metabolism. Provocation with caffeine is used to estimate CYP1A2 activity, but in most tests a long period of caffeine abstinence has to be taken into account. We compared two novel methods with the currently applied test. The pharmacokinetic (PK) parameters of caffeine and paraxanthine were estimated in eight caffeine-taking healthy volunteers by fitting serum concentration-time data to a two-compartment PK model. Then a three-step approach was followed. Step 1: The caffeine administration regimens of three provocation methods, which differ by their periods of abstinence, together with the PK parameters of each volunteer, were entered in a PK simulation program and the molecular ratio of the paraxanthine/caffeine concentration (P/C molratio) of each method was estimated for the individual volunteers. Step 2: For each method a relationship for the population between the caffeine clearance (Clc) and the corresponding P/C molratio was empirically established. Step 3: The true caffeine clearance (Clc tr) of each volunteer, as found by fitting the individual PK curve, was compared for all three methods with the clearance estimated from the individual P/C molratio using the relationship of step 2. The predictive values for Clc of the three methods did not differ significantly from Clc tr. For the three methods the values for bias were 6.7, 4.3 and 3.1%, respectively and for precision they were 12.3, 20.6 and 17.8%. We conclude that the two novel methods of caffeine provocation show good predictive performance for Clc when compared with the conventional method. Abstaining from caffeine for a long period is not necessary to estimate CYP1A2 activity (using the P/C molratio) accurately.