Pharmacokinetics of Ceftaroline in Normal Body Weight and Obese (Classes I, II, and III) Healthy Adult Subjects

ABSTRACTThe pharmacokinetic profile of ceftaroline has not been well characterized in obese adults. The purpose of this study was to evaluate the pharmacokinetics of ceftaroline in 32 healthy adult volunteers aged 18 to 50 years in the normal, overweight, and obese body size ranges. Subjects were evenly assigned to 1 of 4 groups based on their body mass index (BMI) and total body weight (TBW) (ranges, 22.1 to 63.5 kg/m2and 50.1 to 179.5 kg, respectively). Subjects in the lower-TBW groups were matched by age, sex, race/ethnicity, and serum creatinine to the upper-BMI groups. Serial plasma and urine samples were collected over 12 h after the start of the infusion, and the concentrations of ceftaroline fosamil (prodrug), ceftaroline, and ceftaroline M-1 (inactive metabolite) were assayed. Noncompartmental and population pharmacokinetic analyses were used to evaluate the data. The mean plasma ceftaroline maximum concentration and area under the curve were ca. 30% lower in subjects with a BMI of ≥40 kg/m2compared to those <30 kg/m2. A five-compartment pharmacokinetic model with zero-order infusion and first-order elimination optimally described the plasma concentration-time profiles of the prodrug and ceftaroline. Estimated creatinine clearance (eCLCR) and TBW best explained ceftaroline clearance and volume of distribution, respectively. Although lower ceftaroline plasma concentrations were observed in obese subjects, Monte Carlo simulations suggest the probability of target attainment is ≥90% when the MIC is ≤1 μg/ml irrespective of TBW or eCLCR. No dosage adjustment for ceftaroline appears to be necessary based on TBW alone in adults with comparable eCLCR. Confirmation of these findings in infected obese patients is necessary to validate these findings in healthy volunteers. (This study has been registered at ClinicalTrials.gov under registration no. NCT01648127.)

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Pharmacokinetics of Telavancin in Adult Patients with Cystic Fibrosis during Acute Pulmonary Exacerbation

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01914-19 ◽

2019 ◽

Vol 64 (1) ◽

Author(s):

James M. Kidd ◽

Colleen M. Sakon ◽

Louise-Marie Oleksiuk ◽

Jeffrey J. Cies ◽

Rebecca S. Pettit ◽

...

Keyword(s):

Cystic Fibrosis ◽

Body Weight ◽

Total Body Weight ◽

Central Compartment ◽

Volume Of Distribution ◽

Peripheral Compartment ◽

Population Pharmacokinetic ◽

Minimal Risk ◽

Content Type ◽

Total Body

ABSTRACT Adults with cystic fibrosis (CF) frequently harbor Staphylococcus aureus, which is increasingly antibiotic resistant. Telavancin is a once-daily rapidly bactericidal antibiotic active against methicillin-, linezolid-, and ceftaroline-resistant S. aureus. Because CF patients experience alterations in pharmacokinetics, the optimal dose of telavancin in this population is unknown. Adult CF patients (n = 18) admitted for exacerbations received 3 doses of telavancin 7.5 mg/kg of body weight (first 6 patients) or 10 mg/kg (final 12 patients) every 24 h (q24h). Population pharmacokinetic models with and without covariates were fitted using the nonparametric adaptive grid algorithm in Pmetrics. The final model was used to perform 5,000-patient Monte Carlo simulations for multiple telavancin doses. The best fit was a 2-compartment model describing the volume of distribution of the central compartment (Vc) as a multiple of total body weight (TBW) and the volume of distribution of the central compartment scaled to total body weight (Vθ) normalized by the median observed value (Vc = Vθ × TBW/52.1) and total body clearance (CL) as a linear function of creatinine clearance (CRCL) (CL = CLNR + CLθ × CRCL), where CLNR represents nonrenal clearance and CLθ represents the slope term on CRCL to estimate renal clearance. The mean population parameters were as follows: Vθ, 4.92 ± 0.76 liters · kg−1; CLNR, 0.59 ± 0.30 liters · h−1; CLθ, 5.97 × 10−3 ± 1.24 × 10−3; Vp (volume of the peripheral compartment), 3.77 ± 1.41 liters; Q (intercompartmental clearance), 4.08 ± 2.17 liters · h−1. The free area under the concentration-time curve (fAUC) values for 7.5 and 10 mg/kg were 30 ± 4.6 and 52 ± 12 mg · h/liter, respectively. Doses of 7.5 mg/kg and 10 mg/kg achieved 76.5% and 100% probability of target attainment (PTA) at a fAUC/MIC threshold of >215, respectively, for MIC of ≤0.12 mg/liter. The probabilities of reaching the acute kidney injury (AKI) threshold AUC (763 mg · h · liter−1) for these doses were 0% and 0.96%, respectively. No serious adverse events occurred. Telavancin 10 mg/kg yielded optimal PTA and minimal risk of AKI, suggesting that this FDA-approved dose is appropriate to treat acute pulmonary exacerbations in CF adults. (The clinical trial discussed in this study has been registered at ClinicalTrials.gov under identifier NCT03172793.)

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O35 Midazolam pharmacokinetics in children with obesity

Archives of Disease in Childhood ◽

10.1136/archdischild-2019-esdppp.35 ◽

2019 ◽

Vol 104 (6) ◽

pp. e15.2-e16

Author(s):

C Gade ◽

E Sverrisdóttir ◽

K Dalhoff ◽

J Sonne ◽

H Rolighed Christensen ◽

...

Keyword(s):

Body Weight ◽

Status Epilepticus ◽

Intravenous Administration ◽

Plasma Concentrations ◽

Total Body Weight ◽

Volume Of Distribution ◽

Convulsive Status Epilepticus ◽

List Type ◽

Obese Children ◽

Total Body

BackgroundMidazolam is a first-line drug for treatment of status epilepticus,1 2 both by buccal and intravenous administration. In children with obesity, the midazolam pharmacokinetics may be altered, and the current dosing guidelines may therefore be insufficient.The aim of the study was to investigate the pharmacokinetics of midazolam, after intravenous administration, in obese and non-obese children, aged 11–18 years.MethodsTrial subjects were divided into groups by Body Mass Standard Deviation Score (SDS). All children received 1 µg midazolam administered an intravenous bolus dose. Thirteen blood samples were collected per participant at prespecified timepoints over 9 hours. Plasma concentration-time data was fitted to pharmacokinetic models using non-linear mixed effects modelling (NONMEM, 7.4).ResultsSeventy-two children were enrolled in the study, of these 67 children were included in the analysis. The pharmacokinetics of midazolam was best described with a two-compartment model. The changes in pharmacokinetics in children with obesity were best described with a linear function of BMI SDS on inter-compartmental clearance and peripheral volume. Thus, the rate of distribution was faster, and the peripheral volume of distribution was larger in children with obesity as compared to non-obese children. Simulations revealed that long-term infusions based on total body weight, could lead to high plasma concentrations in children with obesity. Furthermore, simulated plasma concentrations after a fixed buccal dose showed that children with obesity may be at risk of subtherapeutic plasma concentrations.ConclusionBMI SDS was shown to have a significant influence on the peripheral volume of distribution and the inter-compartmental clearance of midazolam. The current Danish dosing guidelines for status epilepticus (http://www.paediatri.dk), where midazolam dose is adjusted to total body weight or age, may lead to both supra- and subtherapeutic doses respectively, in children with obesity. However, confirmatory studies are needed.ReferencesSmith R, Brown J. Midazolam for status epilepticus. Aust Prescr. februar 2017;40(1):23–5.Ulvi H, Yoldas T, Müngen B, Yigiter R. Continuous infusion of midazolam in the treatment of refractory generalized convulsive status epilepticus. Neurol Sci Off J Ital Neurol Soc Ital Soc Clin Neurophysiol oktober 2002;23(4):177–82.Disclosure(s)Nothing to disclose

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Development of a Population Pharmacokinetic Model To Describe Azithromycin Whole-Blood and Plasma Concentrations over Time in Healthy Subjects

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02430-12 ◽

2013 ◽

Vol 57 (7) ◽

pp. 3194-3201 ◽

Cited By ~ 10

Author(s):

T. Pene Dumitrescu ◽

T. Anic-Milic ◽

K. Oreskovic ◽

J. Padovan ◽

K. L. R. Brouwer ◽

...

Keyword(s):

Whole Blood ◽

Healthy Subjects ◽

Mononuclear Cells ◽

Plasma Concentrations ◽

Area Under The Curve ◽

Compartment Model ◽

Volume Of Distribution ◽

Population Pharmacokinetic ◽

Polymorphonuclear Cells ◽

Peripheral Blood Mononuclear

ABSTRACTAzithromycin (AZI), a broad-spectrum antibiotic, accumulates in polymorphonuclear cells and peripheral blood mononuclear cells. The distribution of AZI in proinflammatory cells may be important to the anti-inflammatory properties. Previous studies have described plasma AZI pharmacokinetics. The objective of this study was to describe the pharmacokinetics of AZI in whole blood (concentration in whole blood [Cb]) and plasma (concentration in plasma [Cp]) of healthy subjects. In this study, 12 subjects received AZI (500 mg once a day for 3 days). AZICbandCpwere quantified in serial samples collected up to 3 weeks after the last dose and analyzed using noncompartmental and compartmental methods. After the last dose,Cbwas greater thanCp. Importantly,Cb, but notCp, was quantifiable in all but one subject at 3 weeks. The blood area under the curve during a 24-h dosing interval (AUC24) was ∼2-fold greater than the plasma AUC24, but simulations suggested thatCbwas not at steady state by day 3. Upon exploration of numerous models, an empirical 3-compartment model adequately describedCpandCb, butCpwas somewhat underestimated. Intercompartmental clearance (CL; likely representing cells) was lower than apparent oral CL (18 versus 118 liters/h). Plasma, peripheral, and cell compartmental volumes were 439 liters, 2,980 liters, and 3,084 liters, respectively. Interindividual variability in CL was low (26.2%), while the volume of distribution variability was high (107%). This is the first report to describe AZICbin healthy subjects, the distribution parameters betweenCpandCb, and AZI retention in blood for up to 3 weeks following 3 daily doses. The model can be used to predictCbfromCpfor AZI under various dosing regimens. (This study has been registered at ClinicalTrials.gov under registration no. NCT01026064.)

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Novel Population Pharmacokinetic Approach to Explain the Differences between Cystic Fibrosis Patients and Healthy Volunteers via Protein Binding

Pharmaceutics ◽

10.3390/pharmaceutics11060286 ◽

2019 ◽

Vol 11 (6) ◽

pp. 286 ◽

Cited By ~ 2

Author(s):

Nirav Shah ◽

Jürgen Bulitta ◽

Martina Kinzig ◽

Cornelia Landersdorfer ◽

Yuanyuan Jiao ◽

...

Keyword(s):

Cystic Fibrosis ◽

Protein Binding ◽

Healthy Volunteers ◽

Plasma Concentrations ◽

Volume Of Distribution ◽

Population Pharmacokinetic ◽

Unbound Fraction ◽

Low Protein ◽

Novel Approach ◽

Special Patient

The pharmacokinetics in patients with cystic fibrosis (CF) has long been thought to differ considerably from that in healthy volunteers. For highly protein bound β-lactams, profound pharmacokinetic differences were observed between comparatively morbid patients with CF and healthy volunteers. These differences could be explained by body weight and body composition for β-lactams with low protein binding. This study aimed to develop a novel population modeling approach to describe the pharmacokinetic differences between both subject groups by estimating protein binding. Eight patients with CF (lean body mass [LBM]: 39.8 ± 5.4kg) and six healthy volunteers (LBM: 53.1 ± 9.5kg) received 1027.5 mg cefotiam intravenously. Plasma concentrations and amounts in urine were simultaneously modelled. Unscaled total clearance and volume of distribution were 3% smaller in patients with CF compared to those in healthy volunteers. After allometric scaling by LBM to account for body size and composition, the remaining pharmacokinetic differences were explained by estimating the unbound fraction of cefotiam in plasma. The latter was fixed to 50% in male and estimated as 54.5% in female healthy volunteers as well as 56.3% in male and 74.4% in female patients with CF. This novel approach holds promise for characterizing the pharmacokinetics in special patient populations with altered protein binding.

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Vancomycin volume of distribution estimation in adults with class III obesity

American Journal of Health-System Pharmacy ◽

10.1093/ajhp/zxz241 ◽

2019 ◽

Cited By ~ 1

Author(s):

Ryan D Dunn ◽

Ryan L Crass ◽

Joseph Hong ◽

Manjunath P Pai ◽

Lynne C Krop

Keyword(s):

Body Weight ◽

Total Body Weight ◽

Volume Of Distribution ◽

Patient Specific ◽

Pharmacokinetic Analysis ◽

Pharmacokinetic Parameters ◽

Parameter Estimates ◽

Class Iii ◽

Class Iii Obesity ◽

Total Body

Abstract Purpose To compare methods of estimating vancomycin volume of distribution (V) in adults with class III obesity. Methods A retrospective, multicenter pharmacokinetic analysis of adults treated with vancomycin and monitored through measurement of peak and trough concentrations was performed. Individual pharmacokinetic parameter estimates were obtained via maximum a posteriori Bayesian analysis. The relationship between V and body weight was assessed using linear regression. Mean bias and root-mean-square error (RMSE) were calculated to assess the precision of multiple methods of estimating V. Results Of 241 patients included in the study sample, 159 (66.0%) had a BMI of 40.0–49.9 kg/m2, and 82 (34.0%) had a BMI of ≥50.0 kg/m2. The median (5th, 95th percentile) weight of patients was 136 (103, 204) kg, and baseline characteristics were similar between BMI groups. The mean ± S.D. V was lower in patients with a BMI of 40.0–49.9 kg/m2 than in those with a BMI of ≥50.0 kg/m2 (72.4 ± 19.6 L versus 79.3 ± 20.6 L, p = 0.009); however, body size poorly predicted V in regression analyses (R2 < 0.20). A fixed estimate of V (75 L) or use of 0.52 L/kg by total body weight yielded similar bias and error in this population. Conclusion Results of the largest analysis of vancomycin V in class III obesity to date indicated that use of a fixed V value (75 L) and use of a TBW-based estimate (0.52 L/kg) for estimation of vancomycin V in patients with a BMI of ≥40.0 kg/m2 have similar bias. Two postdistribution vancomycin concentrations are needed to accurately determine patient-specific pharmacokinetic parameters, estimate AUC, and improve the precision of vancomycin dosing in this patient population.

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Population Pharmacokinetic Study of Prophylactic Fluconazole in Preterm Infants for Prevention of Invasive Candidiasis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01960-18 ◽

2019 ◽

Vol 63 (6) ◽

Author(s):

Yu Kyong Kim ◽

Juyoung Lee ◽

Jaeseong Oh ◽

Su-jin Rhee ◽

Seung Han Shin ◽

...

Keyword(s):

Body Weight ◽

Preterm Infants ◽

Goodness Of Fit ◽

Pharmacokinetic Model ◽

Dose Interval ◽

Volume Of Distribution ◽

Population Pharmacokinetic ◽

Oral Fluconazole ◽

Systemic Fungal Infection ◽

Population Pharmacokinetic Study

ABSTRACT Fluconazole is an antifungal agent with reported evidence for its prophylactic effect against systemic fungal infection in preterm infants. The aim of this study was to build a population pharmacokinetic model to evaluate the pharmacokinetic characteristics of intravenous and oral fluconazole in preterm infants with the current prophylactic fluconazole dosing regimen. A pharmacokinetic model was developed using 301 fluconazole concentrations from 75 preterm infants with a baseline body weight (WT) ranging from 0.5 to 1.5 kg and an estimated glomerular filtration rate (eGFR) ranging from 12.9 to 58.5 ml/min/1.73 m2. Eligible infants received an intravenous or oral dose of 3 mg/kg of body weight of fluconazole, twice weekly with a ≥72-h dose interval, for 4 weeks. The model was qualified with basic goodness-of-fit diagnostics, visual predictive checks, and bootstrapping. The fluconazole pharmacokinetics was well described with a one-compartment linear model with a proportional residual error. The population clearance (CL) and volume of distribution (V) were derived as 0.0197 × (WT/1.00)0.746 × (eGFR/25.0)0.463 × exp(η) and 1.04 × WT × exp(η), respectively. Such covariate analyses augment the awareness of the need for personalized dosing in preterm infants. (This study has been registered at ClinicalTrials.gov under identifier NCT01683760.)

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The Role of Pharmacokinetics in Anaesthesia: Application to Intravenous Infusions

Anaesthesia and Intensive Care ◽

10.1177/0310057x8701500103 ◽

1987 ◽

Vol 15 (1) ◽

pp. 7-14 ◽

Cited By ~ 5

Author(s):

D. R. Stanski

Keyword(s):

Steady State ◽

Plasma Concentration ◽

Plasma Concentrations ◽

Pharmacokinetic Profile ◽

Volume Of Distribution ◽

Drug Dose ◽

Metabolic Clearance ◽

Drug Infusion ◽

Fixed Rate ◽

Elimination Half

Pharmacokinetic concepts describe the relationship between drug dose and resulting plasma concentration. A drug's pharmacokinetic profile can be described by distribution and elimination half-lives, initial volume of distribution, steady-state distribution volume, and metabolic and distributional clearance. After initiating a fixed rate of drug infusion, four to five terminal elimination half-lives are required to reach a steady state of constant plasma concentration. If a loading dose is given, a steady state can be achieved more rapidly. The most rapid method of achieving a constant plasma concentration involves using a variable rate of drug infusion that adjusts for the metabolic clearance and distribution of the drug. Computer-driven infusion pumps can be used to rapidly achieve, then maintain, constant plasma concentrations of a drug.

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Pharmacokinetics of linezolid for methicillin-resistant Staphylococcus aureus pneumonia in an adult receiving extracorporeal membrane oxygenation

American Journal of Health-System Pharmacy ◽

10.1093/ajhp/zxaa066 ◽

2020 ◽

Vol 77 (11) ◽

pp. 877-881 ◽

Cited By ~ 1

Author(s):

Peter Nikolos ◽

Justin Osorio ◽

Kerry Mohrien ◽

Christina Rose

Keyword(s):

Staphylococcus Aureus ◽

Respiratory Failure ◽

Extracorporeal Membrane Oxygenation ◽

Methicillin Resistant Staphylococcus Aureus ◽

Plasma Concentrations ◽

Area Under The Curve ◽

Volume Of Distribution ◽

Minimum Concentration ◽

Methicillin Resistant ◽

Membrane Oxygenation

Abstract Purpose We present a case of a 55-year-old man post right lung transplantation receiving ECMO for treatment of respiratory failure secondary to methicillin-resistant Staphylococcus aureus (MRSA) pneumonia. Summary Extracorporeal membrane oxygenation (ECMO) is a frequently utilized support therapy for patients with cardiac and/or respiratory failure. Dosing of medications during ECMO can be challenging due to several factors, including sequestration of medications within ECMO circuits, alterations in volume of distribution, and changes in drug clearance. The patient was initiated on empiric antibiotics, then switched to linezolid at a dose of 600 mg every 8 hours. Linezolid plasma concentrations were collected 30 minutes prior to the sixth administered dose and 30 minutes following the 1-hour infusion of the sixth dose, which resulted in values of 0.4 and 1.7 μg/mL, respectively. The ratio of 24-hour area under the curve (AUC0-24) to minimum inhibitory concentration (MIC), assuming a MIC of 2 μg/mL, was calculated using the extrapolated maximum concentration (1.9 μg/mL) and minimum concentration (0.35 μg/mL), resulting in an AUC0-24/MIC value of 10.8. Due to subtherapeutic linezolid plasma concentrations, ceftaroline was initiated and continued for a total of 18 days. To our knowledge, this is the second report to describe inadequate plasma concentrations of linezolid during ECMO. Conclusion In the case described here, linezolid at a dose of 600 mg every 8 hours did not achieve target plasma concentrations in a patient receiving concomitant venovenous ECMO support.

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Is the Recommended Dose of Efavirenz Optimal in Young West African Human Immunodeficiency Virus-Infected Children?

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01594-08 ◽

2009 ◽

Vol 53 (10) ◽

pp. 4407-4413 ◽

Cited By ~ 29

Author(s):

Déborah Hirt ◽

Saik Urien ◽

Mathieu Olivier ◽

Hélène Peyrière ◽

Boubacar Nacro ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Body Weight ◽

Plasma Concentrations ◽

Individual Characteristics ◽

Population Pharmacokinetic ◽

Ratio Test ◽

Time Curve ◽

Once Daily ◽

Concentration Time ◽

Immunodeficiency Virus

ABSTRACT We aimed in this study to describe efavirenz concentration-time courses in treatment-naïve children after once-daily administration to study the effects of age and body weight on efavirenz pharmacokinetics and to test relationships between doses, plasma concentrations, and efficacy. For this purpose, efavirenz concentrations in 48 children were measured after 2 weeks of didanosine-lamivudine-efavirenz treatment, and samples were available for 9/48 children between months 2 and 5 of treatment. Efavirenz concentrations in 200 plasma specimens were measured using a validated high-performance liquid chromatography method. A population pharmacokinetic model was developed with NONMEM. The influence of individual characteristics was tested using a likelihood ratio test. The estimated minimal and maximal concentrations of efavirenz in plasma (C min and C max, respectively) and the area under the concentration-time curve (AUC) were correlated to the decrease in human immunodeficiency virus type 1 RNA levels after 3 months of treatment. The threshold C min (and AUC) that improved efficacy was determined. The target minimal concentration of 4 mg/liter was considered for toxicity. An optimized dosing schedule that would place the highest percentage of children in the interval of effective and nontoxic concentrations was simulated. The pharmacokinetics of efavirenz was best described by a one-compartment model with first-order absorption and elimination. The mean apparent clearance and volume of distribution for efavirenz were 0.211 liter/h/kg and 4.48 liters/kg, respectively. Clearance decreased significantly with age. When the recommended doses were given to 46 of the 48 children, 19% (44% of children weighing less than 15 kg) had C mins below 1 mg/liter. A significantly higher percentage of children with C mins of >1.1 mg/liter or AUCs of >51 mg/liter·h than of children with lower values had viral load decreases greater than 2 log10 copies/ml after 3 months of treatment. Therefore, to optimize the percentage of children with C mins between 1.1 and 4 mg/liter, children should receive the following once-daily efavirenz doses: 25 mg/kg of body weight from 2 to 6 years, 15 mg/kg from 6 to 10 years, and 10 mg/kg from 10 to 15 years. These assumptions should be prospectively confirmed.

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Population Pharmacokinetics of Pyrazinamide in Patients with Tuberculosis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02625-16 ◽

2017 ◽

Vol 61 (6) ◽

Cited By ~ 12

Author(s):

Abdullah Alsultan ◽

Rada Savic ◽

Kelly E. Dooley ◽

Marc Weiner ◽

William Whitworth ◽

...

Keyword(s):

Body Weight ◽

Therapeutic Target ◽

Volume Of Distribution ◽

Current Treatment ◽

Population Pharmacokinetic ◽

Maximum Plasma ◽

Target Attainment ◽

Time Curve ◽

The Mean ◽

Higher Doses

ABSTRACT The current treatment used for tuberculosis (TB) is lengthy and needs to be shortened and improved. Pyrazinamide (PZA) has potent sterilizing activity and has the potential to shorten the TB treatment duration, if treatment is optimized. The goals of this study were (i) to develop a population pharmacokinetic (PK) model for PZA among patients enrolled in PK substudies of Tuberculosis Trial Consortium (TBTC) trials 27 and 28 and (ii) to determine covariates that affect PZA PK. (iii) We also performed simulations and target attainment analysis using the proposed targets of a maximum plasma concentration (C max) of >35 μg/ml or an area under the concentration-versus-time curve (AUC) of >363 μg · h/ml to see if higher weight-based dosing could improve PZA efficacy. Seventy-two patients participated in the substudies. The mean (standard deviation [SD]) C max was 30.8 (7.4) μg/ml, and the mean (SD) AUC from time zero to 24 h (AUC0–24) was 307 (83) μg · h/ml. A one-compartment open model best described PZA PK. Only body weight was a significant covariate for PZA clearance. Women had a lower volume of distribution (V/F) than men, and both clearance (CL/F) and V/F increased with body weight. Our simulations show that higher doses of PZA (>50 mg/kg of body weight) are needed to achieve the therapeutic target of an AUC/MIC of >11.3 in >80% of patients, while doses of >80 mg/kg are needed for target attainment in 90% of patients, given specific assumptions about MIC determinations. For the therapeutic targets of a C max of >35 μg/ml and/or an AUC of >363 μg · h/ml, doses in the range of 30 to 40 mg/kg are needed to achieve the therapeutic target in >90% of the patients. Further clinical trials are needed to evaluate the safety and efficacy of higher doses of PZA.

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