Caspofungin Weight-Based Dosing Supported by a Population Pharmacokinetic Model in Critically Ill Patients

Abstract

<jats:p>The objective of this study was to develop a population pharmacokinetic model and to determine a dosing regimen for caspofungin in critically ill patients. Nine blood samples were drawn per one dosing occasion. Fifteen patients with (suspected) invasive candidasis had one dosing occasion and five had two dosing occasions measured on day 3 (±1) of treatment. Pmetrics was used for population pharmacokinetic modelling and probability of target attainment (PTA). A target 24-hour AUC value of 98 mg*h/L was used as an efficacy parameter. Secondarily the AUC/MIC targets of 450, 865 and 1185 were used to calculate PTAs for <jats:italic>C. glabrata, C. albicans and C. parapsilosis</jats:italic> respectively. The final 2-compartment model included weight as a covariate on volume of distribution (V<jats:sub>d</jats:sub>). The mean V<jats:sub>d</jats:sub> of the central compartment was 7.71 (SD 2.70) L/kg, the mean Ke was 0.09 (SD 0.04) h<jats:sup>-1</jats:sup>, the kcp was 0.44 (SD 0.39) h<jats:sup>-1</jats:sup>, and the kpc was 0.46 (SD 0.35) h<jats:sup>-1</jats:sup>. A loading dose of 2 mg/kg on the first day, followed by 1.25 mg/kg as a maintenance dose was chosen. With this dose, 98% of the patients were expected to reach the AUC target on the first day and 100% of the patients on the third day. The registered caspofungin dose might not be suitable for all overweight (≥120 kg), over 80% of average weight (78 kg), and around 25% of lower weight (≤50 kg) critically ill patients. A weight-based dose regimen might be appropriate for achieving adequate exposure of caspofungin in ICU patients.</jats:p>

Breakthrough invasive fungal infections in liver transplant recipients exposed to prophylaxis with echinocandins vs other antifungal agents: A systematic review and meta‐analysis

“…Consequently, the concept of ‘one size fits all’ guiding dosing recommendations of echinocandins seems to be inappropriate in critically ill OLT recipients 44 . This may possibly explain the trend towards higher risk of breakthrough IFI found in our analysis with echinocandins compared to amphotericin B. Echinocandin dosing adjustment (eg anidulafungin 150 mg/day, micafungin 150–200 mg/day or caspofungin 2 mg/kg loading dose followed by 1.25 mg/kg/day 40,42,43 ) should be implemented in critically ill OLT recipients in order to maximise the achievement of optimal PK/PD target especially against Candida spp., representing a major issue in the immediate post‐transplant period 45 …”

“…Considering that critically ill patients usually exhibit lower serum echinocandin exposure compared to other populations, a more critical and suboptimal concentration are consequently expected in intrabdominal fungal infections. Furthermore, several evidence reported a remarkable echinocandin underexposure both in plasma and surgical site in critically ill patients 40–43 . This may favour the selection of fungi with less echinocandin susceptibility and/or the development of echinocandin resistance 44 .…”

Population Pharmacokinetics of Caspofungin and Dose Simulations in Heart Transplant Recipients

“…Weight was one of the most important covariates that may affect the PK parameters of caspofungin. Several previous studies have identified weight as an important covariate that affects CL and V of caspofungin ( 24 , 25 , 29 ). For example, Hall et al ( 29 ) showed that the V and CL of caspofungin increased with an increase in weight.…”

“…Würthwein et al ( 30 ) found that the weight was most suitable as a covariate for caspofungin CL and V . Märtson et al ( 25 ) proposed a weight-based dose regimen for caspofungin. However, several other studies ( 26 , 31 – 33 ) have found no significant effect of weight on the pharmacokinetic parameters of caspofungin, similar to our research.…”

“…Standard dosing of caspofungin in critically ill patients was associated with low drug exposure and suboptimal therapeutic effects ( 24 ). Studies have identified several variables that may affect the PK parameters of caspofungin in critically ill patients, such as body weight and serum albumin (ALB) concentration ( 25 – 28 ). To the best of our knowledge, no study has reported the PK of caspofungin in HTx recipients.…”