A population pharmacokinetic model to guide clozapine dose selection, based on age, sex, ethnicity, body weight and smoking status

Aims: Guidance on clozapine dosing in treatment-resistant schizophrenia is based largely on data from White young adult males. This study aimed to investigate the pharmacokinetic profiles of clozapine and Ndesmethylclozapine (norclozapine) across the age range, accounting for sex, ethnicity, smoking status, and body weight. Methods: A population pharmacokinetic model, implemented in Monolix, that linked plasma clozapine and norclozapine via a metabolic rate constant, was used to analyse data from a clozapine therapeutic drug monitoring service, 1993–2017. Results: There were 17,787 measurements from 5960 patients (4315 male) aged 18 to 86 years. The estimated clozapine plasma clearance was reduced from 20.2 to 12.0 L h-1 between 20 and 80 years. Model based dose predictions to attain a pre-dose plasma clozapine concentration of 0.35 mg L-1 was 275 (90% prediction interval 125, 625) mg day-1 in a nonsmoking White male weighing 70 kg and aged 40 years. The corresponding predicted dose was increased by 30% in smokers, decreased by 18% in females and was 10% higher and 14% lower in otherwise analogous Afro-Caribbean and Asian patients, respectively. Overall, the predicted dose decreased by 56% between age 20 and 80 years. Conclusion: The large sample size and wide age range of the patients studied allowed precise estimation of dose requirements to attain a pre-dose plasma clozapine concentration of 0.35 mg L-1. The analysis was however limited by the absence of data on clinical outcome and further studies are required to determine optimal pre-dose concentrations specifically in those aged over 65 years

Plasma clozapine and norclozapine after use of either crushed tablets or suspension compared with tablets

Background: With clozapine, either crushed tablets suspended in an aqueous medium or proprietary suspension is sometimes prescribed as an alternative to tablets, but bioequivalence data are scant. Methods: We compared clozapine dose, and plasma clozapine and N-desmethylclozapine (norclozapine) concentrations after use of either tablets or crushed tablets/suspension in samples submitted for clozapine therapeutic drug monitoring, 1993 to 2017. Results: There were 846 patients (1646 samples) given crushed tablets/ suspension and 6065 patients (10,779 samples) given tablets. The median dose (mg d−1 ) was significantly higher in men (500 vs 450) and women (500 vs 400) given crushed tablets/suspension, but the median plasma clo zapine and norclozapine concentrations (mg L−1 ) were significantly lower (men: 0.29 and 0.22 vs 0.39 and 0.28; women: 0.35 and 0.26 vs 0.50 and 0.32, respectively). A subgroup of 480 patients was prescribed either crushed tablets/suspension (1016 samples) or tablets (1259 samples) at dif ferent times. The median dose was again significantly higher in men (500 vs 500) and women (500 vs 450), but the median plasma clozapine and norclozapine concentrations were significantly lower (men: 0.29 and 0.22 vs 0.32 and 0.24; women: 0.30 and 0.24 vs 0.38 and 0.29, respectively). Implications: Poor adherence, sedimentation of suspension before use, and incomplete dosage are potential contributors to the lower median plasma clozapine and norclozapine concentrations observed after use of either crushed clozapine tablets or suspension as compared with tablets. Those administering crushed tablets/suspension should be aware of these factors

Projecting Lifetime Risk of Symptomatic Knee Osteoarthritis and Total Knee Replacement in Individuals Sustaining a Complete Anterior Cruciate Ligament Tear in Early Adulthood.

Objective: To estimate the lifetime risk of knee osteoarthritis (OA) and total knee replacement (TKR) in persons sustaining anterior cruciate ligament (ACL) tear by age 25 years. Methods: We used the Osteoarthritis Policy Model to project the cumulative incidence of symptomatic knee OA requiring TKR in varying situations: no prevalent or incident injury; isolated ACL tear, surgically treated; isolated ACL tear, nonoperatively treated; or a prevalent history or surgically treated ACL and meniscal tear (MT). We estimated MT prevalence and incidence and increased risk of knee OA associated with ACL injury and MT from published literature. We conducted a range of sensitivity analyses to examine the impact of uncertainty in input parameters. Results: Estimated lifetime risk of symptomatic knee OA was 34% for the cohort with ACL injury and MT, compared to 14% for the no-injury cohort. ACL injury without MT was associated with a lifetime risk of knee OA between 16% and 17%, depending on ACL treatment modality. Estimated lifetime risk of TKR ranged from 6% in the no-injury cohort to 22% for the ACL injury and MT cohort. Subjects in the ACL injury and MT cohort developed OA approximately 1.5 years earlier (55.7 versus 57.1) and underwent TKR approximately 2 years earlier (66 versus 68) than the cohort without knee injuries. Conclusion: Sustaining ACL injury early in adulthood leads to greater lifetime risk and earlier onset of knee OA and TKR; concomitant MTs compound this risk. These data provide insight into the impact of sustainable injury prevention interventions in young adults