Population Pharmacokinetics of Escalating Doses of Caspofungin in a Phase II Study of Patients with Invasive Aspergillosis

Würthwein, Gudrun; Cornely, Oliver A.; Trame, Mirjam N.; Vehreschild, Janne; Vehreschild, Maria J. G. T.; Farowski, Fedja; Müller, Carsten; Boos, Joachim; Hempel, Georg; Hallek, Michael; Groll, Andreas H.

doi:10.1128/aac.01912-12

Cited by 44 publications

(30 citation statements)

References 32 publications

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“…This might be due to interaction between caspofungin and cyclosporine A, or changes in plasma composition or saturation of OATP1B1-mediated uptake in liver cells [116,117]. No covariates (e.g., age, gender, creatinine clearance, bilirubin levels) were found to influence the PK of caspofungin in patients with hematological diseases apart from body weight [80,118]. However, the effect of bodyweight is disputable since it is not found in all studies and the effect of body weight on the efficacy of caspofungin remains unclear [80,118].…”

Section: Caspofunginmentioning

confidence: 97%

Impact of special patient populations on the pharmacokinetics of echinocandins

Muilwijk¹,

Lempers²,

Burger³

et al. 2015

Expert Review of Anti-infective Therapy

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Echinocandins belong to the class of antifungal agents. Currently, three echinocandin drugs are licensed for intravenous treatment of invasive fungal infections: anidulafungin, caspofungin and micafungin. While their antifungal activity overlaps, there are substantial differences in pharmacokinetics (PK). Numerous factors may account for variability in PK of echinocandins including age (pediatrics vs adults), body surface area and body composition (normal weight vs obesity), disease status (e.g., critically ill and burn patients) and organ dysfunction (kidney and liver impairment). Subsequent effects of altered exposure might impact efficacy and safety. Knowledge of PK behavior is crucial in optimal clinical utilization of echinocandin in a specific patient or patient population. This review provides up-to-date information on PK data of anidulafungin, caspofungin and micafungin in special patient populations. Patient populations addressed are neonates, children and adolescents, obese patients, patients with hepatic or renal impairment, critically ill patients (including burn patients) and patients with hematological diseases.

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Section: Caspofunginmentioning

confidence: 97%

Impact of special patient populations on the pharmacokinetics of echinocandins

Muilwijk¹,

Lempers²,

Burger³

et al. 2015

Expert Review of Anti-infective Therapy

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“…The pharmacokinetic models used for the study were two previously published 2-compartment population PK models of meropenem (Li et al, 2006) and caspofungin (Würthwein et al, 2013). The patient collective used for the meropenem model comprised of 79 hospitalized patients suffering from different types of infection.…”

Section: Population Pharmacokinetic Modelsmentioning

confidence: 99%

Impact of Inaccurate Documentation of Sampling and Infusion Time in Model-Informed Precision Dosing

et al. 2020

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Background: Routine clinical TDM data is often used to develop population pharmacokinetic (PK) models, which are applied in turn for model-informed precision dosing. The impact of uncertainty in documented sampling and infusion times in population PK modeling and model-informed precision dosing have not yet been systematically evaluated. The aim of this study was to investigate uncertain documentation of (i) sampling times and (ii) infusion rate exemplified with two antiinfectives. Methods: A stochastic simulation and estimation study was performed in NONMEM ® using previously published population PK models of meropenem and caspofungin. Uncertainties, i.e. deviation between accurate and planned sampling and infusion times (standard deviation (SD) ± 5 min to ± 30 min) were added randomly in R before carrying out the simulation step. The estimation step was then performed with the accurate or planned times (replacing real time points by scheduled study values). Relative bias (rBias) and root mean squared error (rRMSE) were calculated to determine accuracy and precision of the primary and secondary PK parameters on the population and individual level. The accurate and the misspecified (using planned sampling times) model were used for Bayesian forecasting of meropenem to assess the impact on PK/PD target calculations relevant to dosing decisions. Results: On the population level, the estimates of the proportional residual error (prop.err.) and the interindividual variability (IIV) on the central volume of distribution (V1) were most affected by erroneous records in the sampling and infusion time (e.g. rBias of prop.err.: 75.5% vs. 183% (meropenem) and 10.1% vs. 109% (caspofungin) for ± 5 vs. ± 30 min, respectively). On the individual level, the rBias of the planned scenario for the typical values V1, Q and V2 increased with increasing uncertainty in time, while CL, AUC and elimination half-life were least affected. Meropenem as a short half-life drug (~1 h) was

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“…In a murine model of IA with escalating doses of caspofungin, Wiederhold et al (37) initially observed a dose-dependent effect, with optimal efficacy on the reduction of pulmonary fungal burden with doses of 1 mg/kg but a significant loss of efficacy at 4 mg/kg. Interestingly, this transitional margin between the optimal and decreased efficacy observed in vitro and in murine models corresponded to the clinical range of therapeutic doses and trough plasma concentrations of caspofungin (38). However, the paradoxical increase in fungal burden observed in vivo does not necessarily correlate with the in vitro paradoxical growth.…”

mentioning

confidence: 94%

Echinocandins for the Treatment of Invasive Aspergillosis: from Laboratory to Bedside

Aruanno

Glampedakis

Lamoth

2019

Antimicrob Agents Chemother

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Echinocandins (caspofungin, micafungin, anidulafungin), targeting ␤-1,3glucan synthesis of the cell wall, represent one of the three currently available antifungal drug classes for the treatment of invasive fungal infections. Despite their limited antifungal activity against Aspergillus spp., echinocandins are considered an alternative option for the treatment of invasive aspergillosis (IA). This drug class exhibits several advantages, such as excellent tolerability and its potential for synergistic interactions with some other antifungals. The objective of this review is to discuss the in vitro and clinical efficacy of echinocandins against Aspergillus spp., considering the complex interactions between the drug, the mold, and the host. The antifungal effect of echinocandins is not limited to direct inhibition of hyphal growth but also induces an immunomodulatory effect on the host's response. Moreover, Aspergillus spp. have developed important adaptive mechanisms of tolerance to survive and overcome the action of echinocandins, such as paradoxical growth at increased concentrations. This stress response can be abolished by several compounds that potentiate the activity of echinocandins, such as drugs targeting the heat shock protein 90 (Hsp90)-calcineurin axis, opening perspectives for adjuvant therapies. Finally, the present and future places of echinocandins as prophylaxis, monotherapy, or combination therapy of IA are discussed in view of the emergence of pan-azole resistance among Aspergillus fumigatus isolates, the occurrence of breakthrough IA, and the advent of new long-lasting echinocandins (rezafungin) or other ␤-1,3-glucan synthase inhibitors (ibrexafungerp). KEYWORDS Aspergillus, anidulafungin, calcineurin, caspofungin, heat shock protein 90, ibrexafungerp, micafungin, paradoxical effect, rezafungin M olds of the genus Aspergillus (particularly, Aspergillus fumigatus) are the causal agents of invasive aspergillosis (IA), a life-threatening infection affecting immunocompromised hosts, such as hematological cancer or transplant patients. The current antifungal armamentarium for the treatment of IA is limited to three antifungal drug classes. Fungicidal drugs, such as the triazoles (e.g., voriconazole, posaconazole, or isavuconazole) and the polyenes (amphotericin B formulations) represent the firstchoice treatments, whereas the fungistatic echinocandins (caspofungin, anidulafungin, and micafungin) represent an alternative and are only marginally used as monotherapy (1, 2). However, use of echinocandins is gaining interest because of the emergence of acquired azole resistance in A. fumigatus isolates and the limitations related to drug interactions and/or toxicity with azoles and amphotericin B. The aim of this review is to discuss the role of the echinocandins in the treatment of IA, from the mechanistic point of view of drug-pathogen-host interactions to clinical application and perspectives. ECHINOCANDINS AGAINST ASPERGILLUSMechanisms of action. The echinocandin drugs are lipopeptides derived from fu...

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Population Pharmacokinetics of Escalating Doses of Caspofungin in a Phase II Study of Patients with Invasive Aspergillosis

Cited by 44 publications

References 32 publications

Impact of special patient populations on the pharmacokinetics of echinocandins

Impact of special patient populations on the pharmacokinetics of echinocandins

Impact of Inaccurate Documentation of Sampling and Infusion Time in Model-Informed Precision Dosing

Echinocandins for the Treatment of Invasive Aspergillosis: from Laboratory to Bedside

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