scholarly journals Population Pharmacokinetics and Cerebrospinal Fluid Penetration of Fluconazole in Adults with Cryptococcal Meningitis

2018 ◽  
Vol 62 (9) ◽  
Author(s):  
Katharine E. Stott ◽  
Justin Beardsley ◽  
Ruwanthi Kolamunnage-Dona ◽  
Anahi Santoyo Castelazo ◽  
Freddie Mukasa Kibengo ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Standard Deviation ◽  
Cryptococcal Meningitis ◽  
Meta Analysis ◽  
Central Compartment ◽  
Order Rate Constant ◽  
Peripheral Compartment ◽  
Population Pharmacokinetic ◽  
Time Curve ◽  
Content Type

ABSTRACTRobust population pharmacokinetic (PK) data for fluconazole are scarce. The variability of fluconazole penetration into the central nervous system (CNS) is not known. A fluconazole PK study was conducted in 43 patients receiving oral fluconazole (usually 800 mg every 24 h [q24h]) in combination with amphotericin B deoxycholate (1 mg/kg q24h) for cryptococcal meningitis (CM). A four-compartment PK model was developed, and Monte Carlo simulations were performed for a range of fluconazole dosages. A meta-analysis of trials reporting outcomes of CM patients treated with fluconazole monotherapy was performed. Adjusted for bioavailability, the PK parameter means (standard deviation) were the following: clearance, 0.72 (0.24) liters/h; volume of the central compartment, 18.07 (6.31) liters; volume of the CNS compartment, 32.07 (17.60) liters; first-order rate constant from the central to peripheral compartment, 12.20 (11.17) h−1, from the peripheral to central compartment, 18.10 (8.25) h−1, from the central to CNS compartment, 35.43 (13.74) h−1, and from the CNS to central the compartment, 28.63 (10.03) h−1. Simulations of the area under concentration-time curve resulted in median (interquartile range) values of 1,143.2 (range, 988.4 to 1,378.0) mg · h/liter in plasma (AUCplasma) and 982.9 (range, 781.0 to 1,185.9) mg · h/liter in cerebrospinal fluid (AUCCSF) after a dosage of 1,200 mg q24h. The mean simulated ratio of AUCCSF/AUCplasmawas 0.89 (standard deviation [SD], 0.44). The recommended dosage of fluconazole for CM induction therapy fails to attain the pharmacodynamic (PD) target in respect to the wild-type MIC distribution forC. neoformans. The meta-analysis suggested modest improvements in both CSF sterility and mortality outcomes with escalating dosage. This study provides the pharmacodynamic rationale for the long-recognized fact that fluconazole monotherapy is an inadequate induction regimen for CM.

scholarly journals Population Pharmacokinetic Model and Meta-analysis of Outcomes of Amphotericin B Deoxycholate Use in Adults with Cryptococcal Meningitis

2018 ◽  
Vol 62 (7) ◽  
Author(s):  
Katharine E. Stott ◽  
Justin Beardsley ◽  
Sarah Whalley ◽  
Freddie Mukasa Kibengo ◽  
Nguyen Thi Hoang Mai ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Rate Constant ◽  
Cryptococcal Meningitis ◽  
Drug Exposure ◽  
Meta Analysis ◽  
Central Compartment ◽  
Order Rate Constant ◽  
Peripheral Compartment ◽  
First Order ◽  
Amphotericin B Deoxycholate

ABSTRACT There is a limited understanding of the population pharmacokinetics (PK) and pharmacodynamics (PD) of amphotericin B deoxycholate (DAmB) for cryptococcal meningitis. A PK study was conducted in n = 42 patients receiving DAmB (1 mg/kg of body weight every 24 h [q24h]). A 2-compartment PK model was developed. Patient weight influenced clearance and volume in the final structural model. Monte Carlo simulations estimated drug exposure associated with various DAmB dosages. A search was conducted for trials reporting outcomes of treatment of cryptococcal meningitis patients with DAmB monotherapy, and a meta-analysis was performed. The PK parameter means (standard deviations) were as follows: clearance, 0.03 (0.01) × weight + 0.67 (0.01) liters/h; volume, 0.82 (0.80) × weight + 1.76 (1.29) liters; first-order rate constant from central compartment to peripheral compartment, 5.36 (6.67) h−1; first-order rate constant from peripheral compartment to central compartment, 9.92 (12.27) h−1. The meta-analysis suggested that the DAmB dosage explained most of the heterogeneity in cerebrospinal fluid (CSF) sterility outcomes but not in mortality outcomes. Simulations of values corresponding to the area under concentration-time curve from h 144 to h 168 (AUC144–168) resulted in median (interquartile range) values of 5.83 mg · h/liter (4.66 to 8.55), 10.16 mg · h/liter (8.07 to 14.55), and 14.51 mg · h/liter (11.48 to 20.42) with dosages of 0.4, 0.7, and 1.0 mg/kg q24h, respectively. DAmB PK is described adequately by a linear model that incorporates weight with clearance and volume. Interpatient PK variability is modest and unlikely to be responsible for variability in clinical outcomes. There is discordance between the impact that drug exposure has on CSF sterility and its impact on mortality outcomes, which may be due to cerebral pathology not reflected in CSF fungal burden, in addition to clinical variables.

scholarly journals Population Pharmacokinetics of Teicoplanin in Preterm and Term Neonates: Is It Time for a New Dosing Regimen?

2020 ◽  
Vol 64 (4) ◽  
Author(s):  
A. Kontou ◽  
K. Sarafidis ◽  
O. Begou ◽  
H. G. Gika ◽  
A. Tsiligiannis ◽  
...  
Keyword(s):  
Creatinine Clearance ◽  
Maintenance Dose ◽  
Plasma Concentrations ◽  
Central Compartment ◽  
Preterm Neonates ◽  
Peripheral Compartment ◽  
Population Pharmacokinetic ◽  
Dosing Regimen ◽  
Time Curve ◽  
Content Type

ABSTRACT Our objective was to develop a population pharmacokinetic (PK) model in order to evaluate the currently recommended dosing regimen in term and preterm neonates. By using an optimal design approach, a prospective PK study was designed and implemented in 60 neonates with postmenstrual ages (PMA) of 26 to 43 weeks. A loading dose of 16 mg/kg was administered at day 1, followed by a maintenance dose of 8 mg/kg daily. Plasma concentrations were quantified by high-pressure liquid chromatography–mass spectrometry. Population PK (popPK) analysis was performed using NONMEM software. Monte-Carlo (MC) simulations were performed to evaluate currently recommended dosing based on a pharmacodynamic index of area under the concentration-time curve (AUC)/MIC ratio of ≥400. A two-compartment model with linear elimination best described the data by the following equations: clearance (CL) = 0.0227 × (weight [wt]/1,765)0.75 × (estimated creatinine clearance [eCRCL]/22)0.672, central compartment volume of distribution (V1) = 0.283 (wt/1,765), intercompartmental clearance (Q) = 0.151 (wt/1,765)0.75, and peripheral compartment volume (V2) = 0.541 (wt/1,765). The interindividual variability estimates for CL, V1, and V2 were 36.5%, 45.7%, and 51.4%, respectively. Current weight (wt) and estimated creatinine clearance (eCRCL) significantly explained the observed variability. MC simulation demonstrated that, with the current dosing regimen, an AUC/MIC ratio of ≥400 was reached by only 68.5% of neonates with wt of <1 kg when the MIC was equal to 1 mg/kg, versus 82.2%, 89.7%, and 92.7% of neonates with wt of 1 to <2, 2 to <3, or ≥3 kg, respectively. Augmentation of a maintenance dose up to 10 or 11 mg/kg for preterm neonates with wt of 1 to <2 or <1 kg, respectively, increases the probability of reaching the therapeutic target; the recommended doses seem to be adequate for neonates with wt of ≥2 kg. Teicoplanin PK are variable in neonates, with wt and eCRCL having the most significant impact. Neonates with wt of <2 kg need higher doses, especially for Staphylococcus spp. with an MIC value of ≥1 mg/liter.

scholarly journals Influence of Experimental Cryptococcal Meningitis in Wistar Rats on Voriconazole Brain Penetration Assessed by Microdialysis

2017 ◽  
Vol 61 (7) ◽  
Author(s):  
Izabel Almeida Alves ◽  
Keli Jaqueline Staudt ◽  
Carolina de Miranda Silva ◽  
Graziela de Araujo Lock ◽  
Teresa Dalla Costa ◽  
...  
Keyword(s):  
Cryptococcal Meningitis ◽  
Free Fraction ◽  
Volume Of Distribution ◽  
Time Profile ◽  
Peripheral Compartment ◽  
Population Pharmacokinetic ◽  
Brain Penetration ◽  
Content Type ◽  
Liquid Chromatography Tandem Mass ◽  
The Impact

ABSTRACT To make advances in the treatment of cryptococcal meningitis, it is crucial to know a given drug's free fraction that reaches the biophase. In the present study, we applied microdialysis (μD) as a tool to determine the free levels reached by voriconazole (VRC) in the brains of healthy and Cryptococcus neoformans-infected rats. The infection was induced by the intravenous (i.v.) administration of 1 × 105 CFU of yeast. The dose administered was 5 mg/kg (of body weight) of VRC, given i.v. Plasma and microdialysate samples were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and LC-UV methods. The free brain/free plasma ratio (fT) and population pharmacokinetic (popPK) analyses were performed to evaluate the impact of infection on PK parameters of the drug. The brain penetration ratio showed an increase on brain exposure in infected animals (fThealthy = 0.85 versus fTinfected = 1.86). The structural PK model with two compartments and Michaelis-Menten (MM) elimination describes the VRC concentration-time profile in plasma and tissue simultaneously. The covariate infection was included in volume of distribution in the peripheral compartment in healthy animals (V 2) and maximum rate of metabolism (VM ). The levels reached in infected tissues were higher than the values described for MIC of VRC for Cryptococccus neoformans (0.03 to 0.5 μg ml−1), indicating its great potential to treat meningitis associated with C. neoformans.

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

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.)

scholarly journals Population Pharmacokinetic Modeling as a Tool To Characterize the Decrease in Ciprofloxacin Free Interstitial Levels Caused by Pseudomonas aeruginosa Biofilm Lung Infection in Wistar Rats

2017 ◽  
Vol 61 (7) ◽  
Author(s):  
Bruna G. S. Torres ◽  
Victória E. Helfer ◽  
Priscila M. Bernardes ◽  
Alexandre José Macedo ◽  
Elisabet I. Nielsen ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Tissue Concentration ◽  
Plasma Concentrations ◽  
Central Compartment ◽  
Population Pharmacokinetic ◽  
Plasma Exposure ◽  
Time Curve ◽  
Content Type ◽  
Population Pharmacokinetic Modeling ◽  
Free Interstitial

ABSTRACT Biofilm formation plays an important role in the persistence of pulmonary infections, for example, in cystic fibrosis patients. So far, little is known about the antimicrobial lung disposition in biofilm-associated pneumonia. This study aimed to evaluate, by microdialysis, ciprofloxacin (CIP) penetration into the lungs of healthy and Pseudomonas aeruginosa biofilm-infected rats and to develop a comprehensive model to describe the CIP disposition under both conditions. P. aeruginosa was immobilized into alginate beads and intratracheally inoculated 14 days before CIP administration (20 mg/kg of body weight). Plasma and microdialysate were sampled from different animal groups, and the observations were evaluated by noncompartmental analysis (NCA) and population pharmacokinetic (popPK) analysis. The final model that successfully described all data consisted of an arterial and a venous central compartment and two peripheral distribution compartments, and the disposition in the lung was modeled as a two-compartment model structure linked to the venous compartment. Plasma clearance was approximately 32% lower in infected animals, leading to a significantly higher level of plasma CIP exposure (area under the concentration-time curve from time zero to infinity, 27.3 ± 12.1 μg · h/ml and 13.3 ± 3.5 μg · h/ml in infected and healthy rats, respectively). Despite the plasma exposure, infected animals showed a four times lower tissue concentration/plasma concentration ratio (lung penetration factor = 0.44 and 1.69 in infected and healthy rats, respectively), and lung clearance (CLlung) was added to the model for these animals (CLlung = 0.643 liters/h/kg) to explain the lower tissue concentrations. Our results indicate that P. aeruginosa biofilm infection reduces the CIP free interstitial lung concentrations and increases plasma exposure, suggesting that plasma concentrations alone are not a good surrogate of lung concentrations.

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

2020 ◽  
Vol 64 (9) ◽  
Author(s):  
Anne-Grete Märtson ◽  
Kim C. M. van der Elst ◽  
Anette Veringa ◽  
Jan G. Zijlstra ◽  
Albertus Beishuizen ◽  
...  
Keyword(s):  
Critically Ill ◽  
Rate Constant ◽  
Critically Ill Patients ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Central Compartment ◽  
Peripheral Compartment ◽  
Population Pharmacokinetic ◽  
Content Type ◽  
The Mean

ABSTRACT 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 dosing occasion. Fifteen patients with (suspected) invasive candidiasis had one dosing occasion and five had two dosing occasions, measured on day 3 (±1) of treatment. Pmetrics was used for population pharmacokinetic modeling and probability of target attainment (PTA). A target 24-h area under the concentration-time curve (AUC) value of 98 mg·h/liter was used as an efficacy parameter. Secondarily, the AUC/MIC targets of 450, 865, and 1,185 were used to calculate PTAs for Candida glabrata, C. albicans, and C. parapsilosis, respectively. The final 2-compartment model included weight as a covariate on volume of distribution (V). The mean V of the central compartment was 7.71 (standard deviation [SD], 2.70) liters/kg of body weight, the mean elimination constant (Ke) was 0.09 (SD, 0.04) h−1, the rate constant for the caspofungin distribution from the central to the peripheral compartment was 0.44 (SD, 0.39) h−1, and the rate constant for the caspofungin distribution from the peripheral to the central compartment was 0.46 (SD, 0.35) h−1. 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 critically ill patients who were all overweight (≥120 kg), over 80% of median weight (78 kg), and around 25% of lower weight (≤50 kg). A weight-based dose regimen might be appropriate for achieving adequate exposure of caspofungin in intensive care unit patients.

scholarly journals Pharmacokinetics of Intravenous and Oral Linezolid in Adults with Cystic Fibrosis

2011 ◽  
Vol 55 (7) ◽  
pp. 3393-3398 ◽  
Author(s):  
Rebecca A. Keel ◽  
Andre Schaeftlein ◽  
Charlotte Kloft ◽  
J. Samuel Pope ◽  
R. Frederic Knauft ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Compartment Model ◽  
Central Compartment ◽  
Time Dependent ◽  
Peripheral Compartment ◽  
Population Pharmacokinetic ◽  
Parameter Estimates ◽  
Content Type ◽  
Mixed Effects Modeling ◽  
Dosing Regimens

ABSTRACTLinezolid is a treatment option for methicillin-resistantStaphylococcus aureus(MRSA) infections in cystic fibrosis (CF) patients. Little is known, however, about its pharmacokinetics in this population. Eight adults with CF were randomized to receive intravenous (i.v.) and oral linezolid at 600 mg twice daily for 9 doses in a crossover design with a 9-day washout. Plasma samples were collected after the first and ninth doses of each phase. Population pharmacokinetic analyses were performed by nonlinear mixed-effects modeling using a previously described 2-compartment model with time-dependent clearance inhibition. Monte Carlo simulation was performed to assess the activities of the linezolid dosing regimens against 42 contemporary MRSA isolates recovered from CF patients. The following pharmacokinetic parameter estimates were observed for the population: absorption rate constant, 1.91 h−1; clearance, 9.54 liters/h; volume of central compartment, 26.8 liters; volume of peripheral compartment, 17.3 liters; and intercompartmental clearance, 104 liters/h. Linezolid demonstrated nonlinear clearance after 9 doses, which was reduced by a mean of 38.9% (range, 28.8 to 59.9%). Mean bioavailability was 85% (range, 47 to 131%). At steady state, 600 mg given twice daily produced 93.0% and 87.2% probabilities of obtaining the target pharmacodynamic exposure against the MRSA isolates for the i.v. and oral formulations, respectively. Thrice-daily dosing increased the probabilities to 97.0% and 95.6%, respectively. Linezolid pharmacokinetics in these adults with CF were well described by a 2-compartment model with time-dependent clearance inhibition. Standard i.v. and oral dosing regimens should be sufficient to reliably attain pharmacodynamic targets against most MRSA isolates; however, more frequent dosing may be required for isolates with MICs of ≥2 μg/ml.

scholarly journals Evaluating the Relationship between Vancomycin Trough Concentration and 24-Hour Area under the Concentration-Time Curve in Neonates

2018 ◽  
Vol 62 (4) ◽  
pp. e01647-17 ◽  
Author(s):  
Sheng-Hsuan Tseng ◽  
Chuan Poh Lim ◽  
Qi Chen ◽  
Cheng Cai Tang ◽  
Sing Teang Kong ◽  
...  
Keyword(s):  
Steady State ◽  
Trough Concentration ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic ◽  
Time Curve ◽  
Content Type ◽  
Concentration Time ◽  
Vancomycin Trough ◽  
Trough Concentrations ◽  
The Relationship

ABSTRACT Bacterial sepsis is a major cause of morbidity and mortality in neonates, especially those involving methicillin-resistant Staphylococcus aureus (MRSA). Guidelines by the Infectious Diseases Society of America recommend the vancomycin 24-h area under the concentration-time curve to MIC ratio (AUC24/MIC) of >400 as the best predictor of successful treatment against MRSA infections when the MIC is ≤1 mg/liter. The relationship between steady-state vancomycin trough concentrations and AUC24 values (mg·h/liter) has not been studied in an Asian neonatal population. We conducted a retrospective chart review in Singapore hospitals and collected patient characteristics and therapeutic drug monitoring data from neonates on vancomycin therapy over a 5-year period. A one-compartment population pharmacokinetic model was built from the collected data, internally validated, and then used to assess the relationship between steady-state trough concentrations and AUC24. A Monte Carlo simulation sensitivity analysis was also conducted. A total of 76 neonates with 429 vancomycin concentrations were included for analysis. Median (interquartile range) was 30 weeks (28 to 36 weeks) for postmenstrual age (PMA) and 1,043 g (811 to 1,919 g) for weight at the initiation of treatment. Vancomycin clearance was predicted by weight, PMA, and serum creatinine. For MRSA isolates with a vancomycin MIC of ≤1, our major finding was that the minimum steady-state trough concentration range predictive of achieving an AUC24/MIC of >400 was 8 to 8.9 mg/liter. Steady-state troughs within 15 to 20 mg/liter are unlikely to be necessary to achieve an AUC24/MIC of >400, whereas troughs within 10 to 14.9 mg/liter may be more appropriate.

scholarly journals Real Life Population Pharmacokinetics Modelling of Eight Factors VIII in Patients with Severe Haemophilia A: Is It Always Relevant to Switch to an Extended Half-Life?

Pharmaceutics ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 380 ◽  
Author(s):  
Quentin Allard ◽  
Zoubir Djerada ◽  
Claire Pouplard ◽  
Yohann Repessé ◽  
Dominique Desprez ◽  
...  
Keyword(s):  
Half Life ◽  
Random Effect ◽  
Real Life ◽  
Compartment Model ◽  
Central Compartment ◽  
Peripheral Compartment ◽  
Population Pharmacokinetic ◽  
Severe Haemophilia ◽  
Fviii Activity ◽  
Data Files

We retrospectively analysed the data files of 171 adults and 87 children/adolescents with severe haemophilia, except for 14 patients (moderate; minor) (1), to develop a global population pharmacokinetic (PK) model for eight factors VIII (FVIII) that could estimate individual PK parameters for targeting the desired level of FVIII activity (FVIII:C); and (2) to compare half-life (HL) in patients switching from a standard half-life (SHL) to an extended half-life (EHL) and evaluate the relevance of the switch. One-stage clotting assay for the measurement of FVIII activity (FVIII:C, IU/mL) was used for population PK modelling. The software, Monolix version 2019R1, was used for non-linear mixed-effects modelling. A linear two-compartment model best described FVIII:C. The estimated PK parameters (between-subject variability) were: 2640 mL (23.2%) for volume of central compartment (V1), 339 mL (46.8%) for volume of peripheral compartment (V2), 135 mL/h for Q (fixed random effect), and 204 mL/h (34.9%) for clearance (Cl). Weight, age, and categorical covariate EHL were found to influence Cl and only weight for V1. This model can be used for all of the FVIII cited in the study. Moreover, we demonstrated, in accordance with previous studies, that Elocta had longer half-life (EHL) than SHL (mean ratio: 1.48) as compared to Advate, Factane, Kogenate, Novoeight, and Refacto.

scholarly journals A Population Pharmacokinetic Modeling Approach Shows that Serum Penicillin G Concentrations Are Below Inhibitory Concentrations by Two Weeks after Benzathine Penicillin G Injection in the Majority of Young Adults

2014 ◽  
Vol 58 (11) ◽  
pp. 6735-6741 ◽  
Author(s):  
Michael Neely ◽  
Edward L. Kaplan ◽  
Jeffrey L. Blumer ◽  
Dennis J. Faix ◽  
Michael P. Broderick
Keyword(s):  
Young Adults ◽  
Central Compartment ◽  
Penicillin G ◽  
Simulated Patients ◽  
Peripheral Compartment ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Data ◽  
Benzathine Penicillin ◽  
Final Population ◽  
Benzathine Penicillin G

ABSTRACTSerum penicillin G falls to low levels 2 weeks after injection as benzathine penicillin G (BPG) in young adults. Using Pmetrics and previously reported penicillin G pharmacokinetic data after 1.2 million units were given as BPG to 329 male military recruits, here we develop the first reported population pharmacokinetic model of penicillin G after BPG injection. We simulated time-concentration profiles over a broad range of pediatric and adult weights after alternative doses and dose frequencies to predict the probability of maintaining serum penicillin G concentrations of >0.02 mg/liter, a proposed protective threshold against group AStreptococcus pyogenes(GAS). The final population model included linear absorption into a central compartment, distribution to and from a peripheral compartment, and linear elimination from the central compartment, with allometrically scaled volumes and rate constants. With 1.2 million units of BPG given intramuscularly every 4 weeks in four total doses, only 23.2% of 5,000 simulated patients maintained serum penicillin G trough concentrations of >0.02 mg/liter 4 weeks after the last dose. When the doses were 1.8 million units and 2.4 million units, the percentages were 30.2% and 40.7%, respectively. With repeated dosing of 1.2 million units every 3 weeks and every 2 weeks for 4 doses, the percentages of simulated patients with a penicillin G trough concentration of >0.02 mg/liter were 37.8% and 65.2%, respectively. Our simulations support recommendations for more frequent rather than higher BPG doses to prevent recurrent rheumatic heart disease in areas of high GAS prevalence or during outbreaks.

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