Keywordscandidiasis; fluconazole; infant; neonate; pharmacology Invasive candidiasis is a leading cause of morbidity and mortality in critically ill infants.1 Prompt administration of antifungal therapy can improve outcomes in candidemic patients. 2 , 3 Despite prompt therapy, 20% of young infants with candidiasis die as a result of invasive disease. 4 , 5 Fluconazole is used frequently in infants for empiric antifungal therapy due to its excellent activity against Candida species, long half life, and low protein binding that allows for high cerebral spinal fluid penetration.6 In adults, effective fluconazole pharmacokinetic/ pharmacodynamic (PK/PD) indices for the treatment of candidiasis have been described.7 -10 A minimum (total drug) area under the curve (AUC) of 400 mg*hr/L ensures that the PK/ PD index of AUC/minimum inhibitory concentration (MIC) stays >50 for Candida species with an MIC breakpoint ≤8 µg/mL.11 -13To reach the drug exposure target AUC of ≥400 mg*hr/L in critically ill infants, dosages of 12 mg/kg/day are recommended.14 Because of the prolonged half life of fluconazole (24 hours), fluconazole dosing of 12 mg/kg/day might delay reaching desired target drug exposure concentrations for 5-7 days.15 For many drugs with prolonged half life, a loading dose is a common strategy to achieve the therapeutic target after the first dose. A loading dose (1600 mg~25 mg/kg) of fluconazole is commonly used in adults with candidemia on the first day of therapy.This loading dose strategy is recommended for adults with candidemia by the Infectious Disease Society of America.16 , 17 Despite frequent use of fluconazole in infants, the PK and safety of a loading dose in infants are not known. The purpose of this study was to Address for correspondence: Danny Benjamin, MD, PhD, MPH, Professor, Duke University, Pediatrics, 2400 Pratt St., Duke Clinical Research Institute, Durham, NC 27715; p: 919-668-8295; f: 919-681-9457; danny.benjamin@duke.edu. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. determine whether a fluconazole loading dose of 25 mg/kg would safely achieve the therapeutic target (AUC of 400 mg*hr/L) after the first day of therapy in young infants at risk of invasive candidiasis. NIH Public Access MATERIALS AND METHODS Study designThis was a prospective, single-center, open-label PK and safety trial of a fluconazole loading dose in infants <60 days of age at Duke University Medical Center in Durham, NC. We recruited subjects from the Pediatric Intensive Care Unit, the Pediatric Cardiac Intensive Care Unit, and the Neonatal Intensive Care Unit. Subjects were given an intravenous lo...

BackgroundThe combination of everolimus and the imidazoquinoline derivative, BEZ235 (dactolisib), a dual PI3K/mTOR inhibitor, demonstrated synergy in a preclinical model.ObjectiveTo establish clinical feasibility, a phase Ib dose-escalation trial investigating safety and pharmacokinetics of this combination in patients with advanced tumors was performed.Patients and MethodsBEZ235 was orally administered daily in escalating doses of 200, 400, and 800 mg along with everolimus at 2.5 mg daily in 28-day cycles. Nineteen patients were enrolled. Adverse events and tumor responses were evaluated using CTCAE v4.0 and RECIST 1.1, respectively. Pharmacokinetic analyses were performed.ResultsCommon toxicities observed included fatigue, diarrhea, nausea, mucositis, and elevated liver enzymes. No confirmed responses were observed. BEZ235 pharmacokinetics exhibited dose-proportional increases in Cmax and AUC0-24 over the three doses, with high inter-individual variability. Non-compartmental and population pharmacokinetic-based simulations indicated significant increases in everolimus Cmax and AUC0-24 on day 28 and decreased clearance to 13.41 L/hr.ConclusionsThe combination of BEZ235 and everolimus demonstrated limited efficacy and tolerance. BEZ235 systemic exposure increased in a dose-proportional manner while oral bioavailability was quite low, which may be related to gastrointestinal-specific toxicity. The changes in steady-state pharmacokinetics of everolimus with BEZ235 highlight potential drug–drug interactions when these two drugs are administered together.Clinicaltrials.gov: NCT01508104 Electronic supplementary materialThe online version of this article (doi:10.1007/s11523-017-0482-9) contains supplementary material, which is available to authorized users.

Acalabrutinib, a selective, covalent Bruton tyrosine kinase inhibitor, is a CYP 3A substrate and weak CYP 3A/ CYP 2C8 inhibitor. A physiologically‐based pharmacokinetic (PBPK) model was developed for acalabrutinib and its active metabolite ACP ‐5862 to predict potential drug–drug interactions ( DDIs ). The model indicated acalabrutinib would not perpetrate a CYP 2C8 or CYP 3A DDI with the sensitive CYP substrates rosiglitazone or midazolam, respectively. The model reasonably predicted clinically observed acalabrutinib DDI with the CYP 3A perpetrators itraconazole (4.80‐fold vs. 5.21‐fold observed) and rifampicin (0.21‐fold vs. 0.23‐fold observed). An increase of two to threefold acalabrutinib area under the curve was predicted for coadministration with moderate CYP 3A inhibitors. When both the parent drug and active metabolite (total active components) were considered, the magnitude of the CYP 3A DDI was much less significant. PBPK dosing recommendations for DDIs should consider the magnitude of the parent drug excursion, relative to safe parent drug exposures, along with the excursion of total active components to best enable safe and adequate pharmacodynamic coverage.

Background Candida infections are a leading cause of infectious disease-related death in infants supported with extracorporeal membrane oxygenation (ECMO). The ECMO circuit can alter drug pharmacokinetics (PK), thus standard fluconazole dosing in children on ECMO may result in suboptimal drug exposure. This study determined the PK of fluconazole in infants on ECMO. Methods Infants <120 days old received either intravenous fluconazole prophylaxis (25 mg/kg once a week) or treatment (12 mg/kg daily) while on ECMO. Paired plasma samples were collected pre- and post-oxygenator around doses 1 and 2 to calculate PK indices and describe oxygenator extraction. A 1-compartment model was fit to the data using non-linear regression. Surrogate pharmacodynamic targets for efficacy were evaluated. Results Ten infants were enrolled. After dose 1 (n=9), the median clearance was 17 mL/kg/h, the median volume of distribution was 1.5 L/kg, and the median exposure in the first 24 hours (AUC0–24) was 322 h*mg/L. After multiple doses (n=7), the median clearance was 22 mL/kg/h, the median volume of distribution was 1.9 L/kg, and the AUC0–24 was 352 h*mg/L. After dose 1, 78% of infants achieved the prophylaxis target, while only 11% achieved the therapeutic target. Oxygenator extraction of fluconazole was minimal (−2.0%, standard deviation 15.0), and extraction was not correlated with age of the ECMO circuit (rho= − 0.05). There were no adverse events related to fluconazole. Conclusions Infants on ECMO had higher volume of distribution but similar clearance when compared with historical controls not on ECMO. In infants on ECMO, a fluconazole dose of 25 mg/kg weekly provides adequate exposure for prophylaxis against Candida infections. However, higher doses may be needed for treatment.

Purpose: To evaluate AZD4635, an adenosine A2A receptor antagonist, as monotherapy or in combination with durvalumab in patients with advanced solid tumors. Experimental design: In phase 1a (dose escalation), patients had relapsed/refractory solid tumors; in phase 1b (dose expansion), patients had checkpoint-inhibitor-naïve metastatic castration-resistant prostate cancer (mCRPC) or colorectal carcinoma (CRC); non-small cell lung cancer (NSCLC) with prior anti-PD-1/PD-L1 exposure; or other solid tumors (checkpoint-naïve or prior anti-PD-1/PD-L1 exposure). Patients received AZD4635 monotherapy (75–200 mg QD or 125 mg BID) or in combination with durvalumab (AZD4635 75 or 100 mg QD). The primary objective was safety; secondary objectives included antitumor activity and pharmacokinetics; exploratory objectives included evaluation of an adenosine gene signature in mCRPC patients. Results: As of September 8, 2020, 250 patients were treated (AZD4635, n=161; AZD4635+durvalumab, n=89). In phase 1a, DLTs were observed with monotherapy (125 mg BID; n=2) and with combination treatment (75 mg; n=1) in patients receiving nanosuspension. The most common treatment-related AEs included nausea, fatigue, vomiting, decreased appetite, dizziness, and diarrhea. The RP2D of the AZD4635 capsule formulation was 75 mg QD, as monotherapy or in combination with durvalumab. The pharmacokinetic profile was dose-proportional, and exposure was adequate to cover target with 100 mg nanosuspension or 75 mg capsule QD. In patients with mCRPC receiving monotherapy or combination treatment, tumor responses (2/39 and 6/37, respectively) and PSA responses (3/60 and 10/45, respectively) were observed. High versus low blood-based adenosine signature was associated with median PFS of 21 weeks versus 8.7 weeks. Conclusions: AZD4635 monotherapy or combination therapy was well-tolerated. Objective responses support additional phase 2 combination studies in mCRPC patients.