Azithromycin To Prevent Bronchopulmonary Dysplasia in Ureaplasma-Infected Preterm Infants: Pharmacokinetics, Safety, Microbial Response, and Clinical Outcomes with a 20-Milligram-per-Kilogram Single Intravenous Dose

ABSTRACTUreaplasmarespiratory tract colonization is associated with bronchopulmonary dysplasia (BPD) in preterm infants. Previously, we demonstrated that a single intravenous (i.v.) dose of azithromycin (10 mg/kg of body weight) is safe but inadequate to eradicateUreaplasmaspp. in preterm infants. We performed a nonrandomized, single-arm open-label study of the pharmacokinetics (PK) and safety of intravenous 20-mg/kg single-dose azithromycin in 13 mechanically ventilated neonates with a gestational age between 24 weeks 0 days and 28 weeks 6 days. Pharmacokinetic data from 25 neonates (12 dosed with 10 mg/kg i.v. and 13 dosed with 20 mg/kg i.v.) were analyzed using a population modeling approach. Using a two-compartment model with allometric scaling of parameters on body weight (WT), the population PK parameter estimates were as follows: clearance, 0.21 liter/h × WT(kg)0.75[WT(kg)0.75indicates that clearance was allometrically scaled on body weight (in kilograms) with a fixed exponent of 0.75]; intercompartmental clearance, 2.1 liters/h × WT(kg)0.75; central volume of distribution (V), 1.97 liters × WT (kg); and peripheralV, 17.9 liters × WT (kg). There was no evidence of departure from dose proportionality in azithromycin exposure over the tested dose range. The calculated area under the concentration-time curve over 24 h in the steady state divided by the MIC90(AUC24/MIC90) for the single dose of azithromycin (20 mg/kg) was 7.5 h. Simulations suggest that 20 mg/kg for 3 days will maintain azithromycin concentrations of >MIC50of 1 μg/ml for this group ofUreaplasmaisolates for ≥96 h after the first dose. Azithromycin was well tolerated with no drug-related adverse events. One of seven (14%)Ureaplasma-positive subjects and three of six (50%)Ureaplasma-negative subjects developed physiologic BPD.Ureaplasmawas eradicated in all treatedUreaplasma-positive subjects. Simulations suggest that a multiple-dose regimen may be efficacious for microbial clearance, but the effect on BPD remains to be determined.

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Pharmacokinetics, Microbial Response, and Pulmonary Outcomes of Multidose Intravenous Azithromycin in Preterm Infants at Risk for Ureaplasma Respiratory Colonization

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.03951-14 ◽

2014 ◽

Vol 59 (1) ◽

pp. 570-578 ◽

Cited By ~ 17

Author(s):

L. Marcela Merchan ◽

Hazem E. Hassan ◽

Michael L. Terrin ◽

Ken B. Waites ◽

David A. Kaufman ◽

...

Keyword(s):

At Risk ◽

Body Weight ◽

Population Pharmacokinetics ◽

Preterm Infants ◽

Volume Of Distribution ◽

Preterm Neonates ◽

Parameter Estimates ◽

Pharmacokinetic Data ◽

Mixed Effect ◽

Content Type

ABSTRACTThe study objectives were to refine the population pharmacokinetics (PK) model, determine microbial clearance, and assess short-term pulmonary outcomes of multiple-dose azithromycin treatment in preterm infants at risk forUreaplasmarespiratory colonization. Fifteen subjects (7 of whom wereUreaplasmapositive) received intravenous azithromycin at 20 mg/kg of body weight every 24 h for 3 doses. Azithromycin concentrations were determined in plasma samples obtained up to 168 h post-first dose by using a validated liquid chromatography-tandem mass spectrometry method. Respiratory samples were obtained predose and at three time points post-last dose forUreaplasmaculture, PCR, antibiotic susceptibility testing, and cytokine concentration determinations. Pharmacokinetic data from these 15 subjects as well as 25 additional subjects (who received either a single 10-mg/kg dose [n= 12] or a single 20-mg/kg dose [n= 13]) were analyzed by using a nonlinear mixed-effect population modeling (NONMEM) approach. Pulmonary outcomes were assessed at 36 weeks post-menstrual age and 6 months adjusted age. A 2-compartment model with all PK parameters allometrically scaled on body weight best described the azithromycin pharmacokinetics in preterm neonates. The population pharmacokinetics parameter estimates for clearance, central volume of distribution, intercompartmental clearance, and peripheral volume of distribution were 0.15 liters/h · kg0.75, 1.88 liters · kg, 1.79 liters/h · kg0.75, and 13 liters · kg, respectively. The estimated area under the concentration-time curve over 24 h (AUC24)/MIC90value was ∼4 h. All posttreatment cultures were negative, and there were no drug-related adverse events. OneUreaplasma-positive infant died at 4 months of age, but no survivors were hospitalized for respiratory etiologies during the first 6 months (adjusted age). Thus, a 3-day course of 20 mg/kg/day intravenous azithromycin shows preliminary efficacy in eradicatingUreaplasmaspp. from the preterm respiratory tract.

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Posaconazole Pharmacodynamic Target Determination against Wild-Type andCyp51Mutant Isolates of Aspergillus fumigatus in anIn VivoModel of Invasive Pulmonary Aspergillosis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01279-12 ◽

2012 ◽

Vol 57 (1) ◽

pp. 579-585 ◽

Cited By ~ 42

Author(s):

Alexander J. Lepak ◽

Karen Marchillo ◽

Jaimie VanHecker ◽

David R. Andes

Keyword(s):

Dose Range ◽

Invasive Pulmonary Aspergillosis ◽

Free Drug ◽

Lung Homogenate ◽

Study Endpoint ◽

Pharmacokinetic Data ◽

Wild Type ◽

Pulmonary Aspergillosis ◽

Time Curve ◽

Content Type

ABSTRACTInvasive pulmonary aspergillosis (IPA) is a devastating disease of immunocompromised patients. Pharmacodynamic (PD) examination of antifungal drug therapy in IPA is one strategy that may improve outcomes. The current study explored the PD target of posaconazole in an immunocompromised murine model of IPA against 10A. fumigatusisolates, including 4Cyp51wild-type isolates and 6 isolates carryingCyp51mutations conferring azole resistance. The posaconazole MIC range was 0.25 to 8 mg/liter. Following infection, mice were given 0.156 to 160 mg/kg of body weight of oral posaconazole daily for 7 days. Efficacy was assessed by quantitative PCR (qPCR) of lung homogenate and survival. At the start of therapy, mice had 5.59 ± 0.19 log10Aspergillusconidial equivalents (CE)/ml of lung homogenate, which increased to 7.11 ± 0.29 log10CE/ml of lung homogenate in untreated animals. The infection was uniformly lethal prior to the study endpoint in control mice. A Hill-type dose response function was used to model the relationship between posaconazole free drug area under the concentration-time curve (AUC)/MIC and qPCR lung burden. The static dose range was 1.09 to 51.9 mg/kg/24 h. The free drug AUC/MIC PD target was 1.09 ± 0.63 for the group of strains. The 1-log kill free drug AUC/MIC was 2.07 ± 1.02. The PD target was not significantly different for the wild-type and mutant organism groups. Mortality mirrored qPCR results, with the greatest improvement in survival noted at the same dosing regimens that produced static or cidal activity. Consideration of human pharmacokinetic data and the current static dose PD target would predict a clinical MIC threshold of 0.25 to 0.5 mg/liter.

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Comparative Pharmacodynamics of Telavancin and Vancomycin in the Neutropenic Murine Thigh and Lung Infection Models against Staphylococcus aureus

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00281-17 ◽

2017 ◽

Vol 61 (7) ◽

Cited By ~ 14

Author(s):

Alexander J. Lepak ◽

Miao Zhao ◽

David R. Andes

Keyword(s):

Staphylococcus Aureus ◽

Dose Range ◽

Lung Infection ◽

Free Drug ◽

Lung Model ◽

Maximum Effect ◽

Pharmacokinetic Data ◽

Time Curve ◽

Content Type ◽

Infection Models

ABSTRACT The pharmacodynamics of telavancin and vancomycin were compared using neutropenic murine thigh and lung infection models. Four Staphylococcus aureus strains were included. The telavancin MIC ranged from 0.06 to 0.25 mg/liter, and the vancomycin MIC ranged from 1 to 4 mg/liter. The plasma pharmacokinetics of escalating doses (1.25, 5, 20, and 80 mg/kg of body weight) of telavancin and vancomycin were linear over the dose range. Epithelial lining fluid (ELF) pharmacokinetics for each drug revealed that penetration into the ELF mirrored the percentage of the free fraction (the fraction not protein bound) in plasma for each drug. Telavancin (0.3125 to 80 mg/kg/6 h) and vancomycin (0.3125 to 1,280 mg/kg/6 h) were administered by the subcutaneous route in treatment studies. Dose-dependent bactericidal activity against all four strains was observed in both models. A sigmoid maximum-effect model was used to determine the area under the concentration-time curve (AUC)/MIC exposure associated with net stasis and 1-log10 kill relative to the burden at the start of therapy. The 24-h plasma free drug AUC (fAUC)/MIC values associated with stasis and 1-log kill were remarkably congruent. Net stasis for telavancin was noted at fAUC/MIC values of 83 and 40.4 in the thigh and lung, respectively, and 1-log kill was noted at fAUC/MIC values of 215 and 76.4, respectively. For vancomycin, the fAUC/MIC values for stasis were 77.9 and 45.3, respectively, and those for 1-log kill were 282 and 113, respectively. The 24-h ELF total drug AUC/MIC targets in the lung model were very similar to the 24-h plasma free drug AUC/MIC targets for each drug. Integration of human pharmacokinetic data for telavancin, the results of the MIC distribution studies, and the pharmacodynamic targets identified in this study suggests that the current dosing regimen of telavancin is optimized to obtain drug exposures sufficient to treat S. aureus infections.

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Isavuconazole Pharmacodynamic Target Determination for Candida Species in anIn VivoMurine Disseminated Candidiasis Model

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01354-13 ◽

2013 ◽

Vol 57 (11) ◽

pp. 5642-5648 ◽

Cited By ~ 37

Author(s):

Alexander J. Lepak ◽

Karen Marchillo ◽

Jamie VanHecker ◽

Daniel Diekema ◽

David R. Andes

Keyword(s):

Body Weight ◽

Dose Range ◽

Clinical Trial Data ◽

Free Drug ◽

Time Curve ◽

Content Type ◽

Disseminated Candidiasis ◽

Elimination Half ◽

The Mean ◽

Species Specific

ABSTRACTPharmacodynamic (PD) studies with triazoles in the neutropenic murine disseminated candidiasis model have been performed extensively forCandida albicans. They have consistently shown that the pharmacodynamic index most closely correlated with efficacy is the ratio of the 24-h area under the concentration-time curve (AUC) to the MIC, and a target 24-h free-drug AUC/MIC ratio near 25 is associated with 50% of maximal microbiologic efficacy. We utilized this model to investigate the pharmacodynamics of isavuconazole. Isavuconazole pharmacokinetics were linear over the dose range studied. Oral-gastric doses of 640, 160, 40, and 10 mg of prodrug/kg of body weight produced peak levels of 0.51 to 25.4 mg/liter, an elimination half-life of 1 to 5 h, and an AUC from 0 h to infinity (AUC0-∞) of 0.9 to 287 mg · h/liter. The AUC/MIC ratio was the pharmacodynamic index that correlated best with efficacy (R2, 0.84). Pharmacodynamic target studies were performed using 4C. albicansisolates with both a 24-h and a 96-h treatment duration. The strains were chosen to include previously characterized fluconazole-resistant strains. The mean 50% effective doses (ED50) (expressed in mg/kg of body weight/12 h) and associated 24-h free-drug AUC/MIC ratios were 89.3 ± 46.7 and 67.7 ± 35 for the 24-h treatment and 59.6 ± 22 and 33.3 ± 25.5 for the 96-h treatment. These differences were not statistically significant. Pharmacodynamic targets for two non-albicans Candidaspecies were also explored. The mean ED50(expressed in mg/kg/12 h) and associated 24-h free-drug AUC/MIC ratios were 31.2 and 6.2 forCandida tropicalis(n= 1) and 50.5 and 1.6 forCandida glabrata(n= 2). These PD targets were significantly different fromC. albicanstargets (P, 0.04). Isavuconazole PD targets forC. albicansare similar to those observed in this model with other triazoles. However, the PD targets for non-albicans Candidaspecies were more than 10-fold lower than those forC. albicans(P, 0.04). This difference is similar to the species-specific PD relationships for the echinocandins. The lower PD targets for these species in this model will be important to consider in the analysis of clinical trial data and during the development of susceptibility breakpoints.

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Population Pharmacokinetics of Micafungin and Its Metabolites M1 and M5 in Children and Adolescents

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.03736-14 ◽

2014 ◽

Vol 59 (2) ◽

pp. 905-913 ◽

Cited By ~ 21

Author(s):

William W. Hope ◽

Atsunori Kaibara ◽

Michael Roy ◽

Antonio Arrieta ◽

Nkechi Azie ◽

...

Keyword(s):

Body Weight ◽

Invasive Candidiasis ◽

Phase Iii ◽

Target Range ◽

Pharmacokinetic Parameters ◽

Population Pharmacokinetic ◽

Pharmacokinetic Data ◽

Two Phase ◽

Time Curve ◽

Content Type

ABSTRACTThe aim of this analysis was to identify therapeutic micafungin regimens for children that produce the same micafungin exposures known to be effective for the prevention and treatment ofCandidainfections in adults. Pediatric pharmacokinetic data from 229 patients between the ages of 4 months and <17 years were obtained from four phase I and two phase III clinical trials. Population pharmacokinetic models were used to simulate the proportion of children who had a steady-state area under the concentration-time curve at 24 hours (AUC24) of micafungin within the 10th to 90th percentile range observed in a population of adults receiving a dose of micafungin with established efficacy for invasive candidiasis (100 mg/day), i.e., 75 to 139 μg · h/ml. Simulated pediatric dosages of 0.5 to 5 mg/kg of body weight/day were explored. A two-compartment model was used that incorporated body weight as a predefined covariate for allometric scaling of the pharmacokinetic parameters. During construction of the model, aspartate aminotransferase and total bilirubin were also identified as covariates that had a significant effect on micafungin clearance. A dose of 2 mg/kg resulted in the highest proportion of children within the predefined micafungin AUC24target range for invasive candidiasis. Cutoffs of 40 or 50 kg for weight-based dosing resulted in heavier children being appropriately dosed. Thus, dose regimens of 1, 2, and 3 mg/kg/day micafungin are appropriate for the prevention of invasive candidiasis, the treatment of invasive candidiasis, and the treatment of esophageal candidiasis, respectively, in children aged 4 months to <17 years.

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Pharmacokinetics of Telavancin at Fixed Doses in Normal-Body-Weight and Obese (Classes I, II, and III) Adult Subjects

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02475-17 ◽

2018 ◽

Vol 62 (4) ◽

Cited By ~ 2

Author(s):

Kristen L. Bunnell ◽

Manjunath P. Pai ◽

Monica Sikka ◽

Susan C. Bleasdale ◽

Eric Wenzler ◽

...

Keyword(s):

Body Weight ◽

Time Profile ◽

Primary Objective ◽

Fixed Dose ◽

Target Area ◽

Obese Patients ◽

Time Curve ◽

Content Type ◽

Time Zero ◽

Concentration Time

ABSTRACT A recommended total-body-weight (TBW) dosing strategy for telavancin may not be optimal in obese patients. The primary objective of this study was to characterize and compare the pharmacokinetics (PK) of telavancin across four body size groups: normal to overweight and obese classes I, II, and III. Healthy adult subjects ( n = 32) received a single, weight-stratified, fixed dose of 500 mg ( n = 4), 750 mg ( n = 8), or 1,000 mg ( n = 20) of telavancin. Noncompartmental PK analyses revealed that subjects with a body mass index (BMI) of ≥40 kg/m 2 had a higher volume of distribution (16.24 ± 2.7 liters) than subjects with a BMI of <30 kg/m 2 (11.71 ± 2.6 liters). The observed area under the concentration-time curve from time zero to infinity (AUC 0–∞ ) ranged from 338.1 to 867.3 mg · h/liter, with the lowest exposures being in subjects who received 500 mg. AUC 0–∞ values were similar among obese subjects who received 1,000 mg. A two-compartment population PK model best described the plasma concentration-time profile of telavancin when adjusted body weight (ABW) was included as a predictive covariate. Fixed doses of 750 mg and 1,000 mg had similar target attainment probabilities for efficacy as doses of 10 mg/kg of body weight based on ABW and TBW, respectively. However, the probability of achieving a target area under the concentration-time curve from time zero to 24 h of ≥763 mg · h/liter in association with acute kidney injury was highest (19.7%) with TBW-simulated dosing and lowest (0.4%) at the 750-mg dose. These results suggest that a fixed dose of 750 mg is a safe and effective alternative to telavancin doses based on TBW or ABW for the treatment of obese patients with normal renal function and Staphylococcus aureus infections. (This study has been registered at ClinicalTrials.gov under identifier NCT02753855.)

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Population Pharmacokinetics and Dosing Optimization of Azithromycin in Children with Community-Acquired Pneumonia

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00686-18 ◽

2018 ◽

Vol 62 (9) ◽

Cited By ~ 3

Author(s):

Yi Zheng ◽

Shu-Ping Liu ◽

Bao-Ping Xu ◽

Zhong-Ren Shi ◽

Kai Wang ◽

...

Keyword(s):

Body Weight ◽

Population Pharmacokinetics ◽

Pediatric Patients ◽

Community Acquired Pneumonia ◽

Pharmacodynamic Modeling ◽

Pharmacokinetic Data ◽

Loading Dose ◽

Dosing Regimen ◽

Time Curve ◽

Dose Strategy

ABSTRACT Azithromycin is extensively used in children with community-acquired pneumonia (CAP). Currently, the intravenous azithromycin is used off-label in children partly due to lacking of pharmacokinetic data. Our objective was to evaluate the population pharmacokinetics (PPK) and optimize dose strategy in order to improve treatment in this distinctive population. This was a prospective, multicenter, open-labeled pharmacokinetic study. Blood samples were collected from hospitalized pediatric patients and concentrations were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). PPK analysis was conducted using NONMEM software. The pharmacokinetic data from 95 pediatric patients (age range, 2.1 to 11.7 years) were available for analysis. The PPK was best fitted by a two-compartment model with linear elimination. Covariate analysis verified that body weight and alanine aminotransferase (ALT) had significant effects on azithromycin pharmacokinetics, yielding a 24% decrease of clearance in patients with ALT of >40. Monte Carlo simulation showed that for children with normal liver function, a loading-dose strategy (a loading dose of 15 mg/kg of body weight followed by maintenance doses of 10 mg/kg) would achieve the ratio of the area under free drug plasma concentration-time curve over 24 h (fAUC) to MIC90 (fAUC/MIC) target of 3 h in 53.2% of hypothetical patients, using a normative MIC susceptibility breakpoint of 2 mg/liter. For children with ALT of >40, the proposed dose needed to decrease by 15% to achieve comparable exposure. The corresponding risk of overdose for the recommended dosing regimen was less than 5.8%. In conclusion, the PPK of azithromycin was evaluated in children with CAP and an optimal dosing regimen was constructed based on developmental pharmacokinetic-pharmacodynamic modeling and simulation.

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Open-Label Crossover Study of Primaquine and Dihydroartemisinin-Piperaquine Pharmacokinetics in Healthy Adult Thai Subjects

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.03704-14 ◽

2014 ◽

Vol 58 (12) ◽

pp. 7340-7346 ◽

Cited By ~ 32

Author(s):

Borimas Hanboonkunupakarn ◽

Elizabeth A. Ashley ◽

Podjanee Jittamala ◽

Joel Tarning ◽

Sasithon Pukrittayakamee ◽

...

Keyword(s):

Crossover Study ◽

Hospital Admissions ◽

Geometric Mean ◽

Radical Cure ◽

Open Label ◽

Time Curve ◽

Content Type ◽

Concentration Time ◽

Pharmacokinetic Assessment ◽

Adult Volunteers

ABSTRACTDihydroartemisinin-piperaquine is an artemisinin-based combination treatment (ACT) recommended by the WHO for uncomplicatedPlasmodium falciparummalaria, and it is being used increasingly for resistant vivax malaria where combination with primaquine is required for radical cure. The WHO recently reinforced its recommendations to add a single dose of primaquine to ACTs to reduceP. falciparumtransmission in low-transmission settings. The pharmacokinetics of primaquine and dihydroartemisinin-piperaquine were evaluated in 16 healthy Thai adult volunteers in a randomized crossover study. Volunteers were randomized to two groups of three sequential hospital admissions to receive 30 mg (base) primaquine, 3 tablets of dihydroartemisinin-piperaquine (120/960 mg), and the drugs together at the same doses. Blood sampling was performed over 3 days following primaquine and 36 days following dihydroartemisinin-piperaquine dosing. Pharmacokinetic assessment was done with a noncompartmental approach. The drugs were well tolerated. There were no statistically significant differences in dihydroartemisinin and piperaquine pharmacokinetics with or without primaquine. Dihydroartemisinin-piperaquine coadministration significantly increased plasma primaquine levels; geometric mean ratios (90% confidence interval [CI]) of primaquine combined versus primaquine alone for maximum concentration (Cmax), area under the concentration-time curve from 0 h to the end of the study (AUC0–last), and area under the concentration-time curve from 0 h to infinity (AUC0–∞) were 148% (117 to 187%), 129% (103 to 163%), and 128% (102 to 161%), respectively. This interaction is similar to that described recently with chloroquine and may result in an enhanced radical curative effect. (This study has been registered at ClinicalTrials.gov under registration no. NCT01525511.)

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81 Bioequivalence of a Manipulation-Resistant Immediate-Release Amphetamine Sulfate Formulation Compared with Reference Standard

CNS Spectrums ◽

10.1017/s1092852919000609 ◽

2019 ◽

Vol 24 (1) ◽

pp. 216-216

Author(s):

Steve Caras ◽

Terrilyn Sharpe

Keyword(s):

Single Dose ◽

Healthy Volunteers ◽

Peak Concentration ◽

Immediate Release ◽

Open Label ◽

Time Curve ◽

Time To Peak ◽

Amphetamine Sulfate ◽

Quantifiable Concentration ◽

Funding Acknowledgements

AbstractStudy ObjectivesWe compared the bioavailability of racemic amphetamine (d-amphetamine and l-amphetamine) from a manipulation-resistant immediate-release (IR) amphetamine sulfate capsule (AR19) versus amphetamine sulfate IR tablets (reference).MethodIn this open-label, randomized, two-period, two-treatment, two-sequence, crossover study, 36 healthy volunteers aged 18–45 received a single dose (20-mg capsule) of AR19 in one period and a single dose (2 x 10-mg tablets) of reference in another period, after a 10-hour overnight fast. Each drug administration was separated by a washout period of at least 6days. Bioequivalence for d- and l-amphetamine was assessed using time to peak concentration (Tmax), peak concentration in plasma (Cmax), and area under the plasma concentration–time curve from time-zero to the time of the last quantifiable concentration (AUClast) and extrapolated to infinity (AUCinf).ResultsAll 36 volunteers completed both treatment sequences. Mean (standard deviation; SD) Tmax for d- and l-amphetamine was similar for AR19 (2.84[1.05]; 3.05[1.22], respectively) and reference (2.52[0.75]; 2.75[1.00], respectively). The geometric least-squares mean ratios and 90% confidence intervals were within the boundary of 80%–125% for bioequivalence for Cmax (d-amphetamine, 98.35% [96.12–100.64]; l-amphetamine, 98.82% [96.42–101.28]), AUClast (d-amphetamine, 99.45% [96.92–102.05]; l-amphetamine, 99.29% [96.55–102.10]), and AUCinf (d-amphetamine, 99.50%[96.77–102.30]; l-amphetamine, 99.23% [96.06–102.50]). A total of 13 mild adverse events were reported by 7 volunteers (AEs; AR19, n=5; reference, n=8). No serious AEs were reported.ConclusionAR19 was well tolerated and was bioequivalent to reference when administered as a 20-mg dose in healthy volunteers.Funding Acknowledgements: This study was funded by Arbor Pharmaceuticals, LLC.

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Isavuconazole Population Pharmacokinetic Analysis Using Nonparametric Estimation in Patients with Invasive Fungal Disease (Results from the VITAL Study)

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00514-16 ◽

2016 ◽

Vol 60 (8) ◽

pp. 4568-4576 ◽

Cited By ~ 34

Author(s):

Laura L. Kovanda ◽

Amit V. Desai ◽

Qiaoyang Lu ◽

Robert W. Townsend ◽

Shahzad Akhtar ◽

...

Keyword(s):

Nonparametric Estimation ◽

Invasive Fungal Disease ◽

Fungal Disease ◽

Water Soluble ◽

Pharmacokinetic Analysis ◽

Population Pharmacokinetic ◽

Dosing Regimen ◽

Open Label ◽

Time Curve ◽

Content Type

ABSTRACTIsavuconazonium sulfate (Cresemba; Astellas Pharma Inc.), a water-soluble prodrug of the triazole antifungal agent isavuconazole, is available for the treatment of invasive aspergillosis (IA) and invasive mucormycosis. A population pharmacokinetic (PPK) model was constructed using nonparametric estimation to compare the pharmacokinetic (PK) behaviors of isavuconazole in patients treated in the phase 3 VITAL open-label clinical trial, which evaluated the efficacy and safety of the drug for treatment of renally impaired IA patients and patients with invasive fungal disease (IFD) caused by emerging molds, yeasts, and dimorphic fungi. Covariates examined were body mass index (BMI), weight, race, impact of estimated glomerular filtration rate (eGFR) on clearance (CL), and impact of weight on volume. PK parameters were compared based on IFD type and other patient characteristics. Simulations were performed to describe the MICs covered by the clinical dosing regimen. Concentrations (n= 458) from 136 patients were used to construct a 2-compartment model (first-order absorption compartment and central compartment). Weight-related covariates affected clearance, but eGFR did not. PK parameters and intersubject variability of CL were similar across different IFD groups and populations. Target attainment analyses demonstrated that the clinical dosing regimen would be sufficient for total drug area under the concentration-time curve (AUC)/MIC targets ranging from 50.5 forAspergillusspp. (up to the CLSI MIC of 0.5 mg/liter) to 270 and 5,053 forCandida albicans(up to MICs of 0.125 and 0.004 mg/liter, respectively) and 312 for non-albicans Candidaspp. (up to a MIC of 0.125 mg/liter). The estimations forCandidaspp. were exploratory considering that no patients withCandidainfections were included in the current analyses. (The VITAL trial is registered at ClinicalTrials.gov under number NCT00634049.)

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