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 Population Pharmacokinetics Analysis To Inform Efavirenz Dosing Recommendations in Pediatric HIV Patients Aged 3 Months to 3 Years

2016 ◽  
Vol 60 (6) ◽  
pp. 3676-3686 ◽  
Author(s):  
Man Luo ◽  
Sunny Chapel ◽  
Heather Sevinsky ◽  
Ishani Savant ◽  
Brenda Cirincione ◽  
...  
Keyword(s):  
Pediatric Patients ◽  
Pediatric Population ◽  
The United States ◽  
Volume Of Distribution ◽  
Time Profile ◽  
Pediatric Hiv ◽  
Target Range ◽  
Population Pharmacokinetic ◽  
The European Union ◽  
The Impact

Efavirenz (EFV) is a nonnucleoside reverse transcriptase inhibitor approved worldwide for the treatment of HIV in adults and children over 3 years of age or weighing over 10 kg. Only recently EFV was approved in children over 3 months and weighing at least 3.5 kg in the United States and the European Union. The objective of this analysis was to support the selection of an appropriate dose for this younger pediatric population and to explore the impact of CYP2B6 genetic polymorphisms on EFV systemic exposures. A population pharmacokinetic (PPK) model was developed using data from three studies in HIV-1-infected pediatric subjects (n= 168) and one study in healthy adults (n= 24). The EFV concentration-time profile was best described by a two-compartment model with first-order absorption and elimination. Body weight was identified as a significant predictor of efavirenz apparent clearance (CL), oral central volume of distribution (VC), and absorption rate constant (Ka). The typical values of efavirenz apparent CL,VC, oral peripheral volume of distribution (VP), andKafor a reference pediatric patient were 4.8 liters/h (4.5 to 5.1 liters/h), 84.9 liters (76.8 to 93.0 liters), 287 liters (252.6 to 321.4 liters), and 0.414 h−1(0.375 to 0.453 h−1), respectively. The final model was used to simulate steady-state efavirenz concentrations in pediatric patients weighing <10 kg to identify EFV doses that produce comparable exposure to adult and pediatric patients weighing ≥10 kg. Results suggest that administration of EFV doses of 100 mg once daily (QD) to children weighing ≥3.5 to <5 kg, 150 mg QD to children weighing ≥5 to <7.5 kg, and 200 mg QD to children weighing ≥7.5 to <10 kg produce exposures within the target range. Further evaluation of the impact of CYP2B6 polymorphisms on EFV PK showed that the identification of CYP2B6 genetic status is not predictive of EFV exposure and thus not informative to guide pediatric dosing regimens.

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 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.

Population Pharmacokinetic Modeling in Very Premature Infants Receiving Midazolam during Mechanical Ventilation 

1999 ◽  
Vol 90 (2) ◽  
pp. 451-457 ◽  
Author(s):  
Toong C. Lee ◽  
Bruce G. Charles ◽  
Glen J. Harte ◽  
Peter H. Gray ◽  
Peter A. Steer ◽  
...  
Keyword(s):  
Mechanical Ventilation ◽  
Population Pharmacokinetics ◽  
Premature Infants ◽  
Coefficient Of Variation ◽  
Population Analysis ◽  
Volume Of Distribution ◽  
Continuous Treatment ◽  
Peripheral Compartment ◽  
Population Pharmacokinetic ◽  
Very Premature Infants

Background Midazolam is used widely as a sedative to facilitate mechanical ventilation. This prospective study investigated the population pharmacokinetics of midazolam in very premature infants. Methods Midazolam (100 microg/kg) was administered as a rapid intravenous bolus dose every 4-6 h to 60 very premature neonates with a mean (range) gestational age of 27 weeks (24-31 weeks), a birth weight of 965 g (523-1,470 g), and an age of 4.5 days (2-15 days). A median (range) of four (one to four) blood samples, 0.2 ml each, were drawn at random times after the first dose or during continuous treatment, and concentrations of midazolam in serum were assayed by high-performance liquid chromatography. A population analysis was conducted using a two-compartment pharmacokinetic model using the NONMEM program. Results Average parameter values (interpatient percent coefficient of variation) for infants with birth weights 1,000 g or less were total systemic clearance (Cl(T)) = 0.783 ml/min (83%), intercompartmental clearance (Cl(Q)) = 6.53 ml/min (116%), volume of distribution of the central compartment (V1) = 473 ml (70%), and volume of distribution of the peripheral compartment (V2) = 513 ml (146%). For infants with birth weights more than 1,000 g they were as follows: Cl(T) = 1.24 ml/min (78%), Cl(Q) = 9.82 ml/min (98%), V1 = 823 ml (43%), and V2 = 1,040 ml (193%). The intrapatient variability (percent coefficient of variation) in the data was 4.5% at the mean concentration midazolam in serum of 121 ng/mL. Conclusions Serum concentration-time data were used in modeling the population pharmacokinetics of midazolam in very premature, ventilated neonates. Clearance of midazolam was markedly decreased compared with previous data from term infants and older patients. Infants weighing less than 1,000 g at birth had significantly lower clearance than those weighing more than 1,000 g.

scholarly journals Baculovirus Per Os Infectivity Factor Complex: Components and Assembly

2019 ◽  
Vol 93 (6) ◽  
Author(s):  
Xi Wang ◽  
Yu Shang ◽  
Cheng Chen ◽  
Shurui Liu ◽  
Meng Chang ◽  
...  
Keyword(s):  
Polyacrylamide Gel Electrophoresis ◽  
Critical Role ◽  
Previous Knowledge ◽  
Multiprotein Complex ◽  
Core Complex ◽  
Insect Midgut ◽  
Content Type ◽  
The Core ◽  
Liquid Chromatography Tandem Mass ◽  
The Impact

ABSTRACT Baculovirus entry into insect midgut cells is dependent on a multiprotein complex of per os infectivity factors (PIFs) on the envelopes of occlusion-derived virions (ODVs). The structure and assembly of the PIF complex are largely unknown. To reveal the complete members of the complex, a combination of blue native polyacrylamide gel electrophoresis, liquid chromatography-tandem mass spectrometry, and Western blotting was conducted on three different baculoviruses. The results showed that the PIF complex has a molecular mass of ∼500 kDa and consists of nine PIFs, including a newly discovered member (PIF9). To decipher the assembly process, each pif gene was knocked out from the Autographa californica multicapsid nucleopolyhedrovirus (AcMNPV) genome individually by use of synthetic baculovirus technology, and the impact on PIF complex formation was investigated. Deletion of pif8 resulted in the formation of an ∼400-kDa subcomplex. Deletion of pif0, -4, -6, -7, or -9 resulted in a subcomplex of ∼230 kDa, but deletion of pif1, -2, or -3 abolished formation of any complex. Taken together, our data identified a core complex of ∼230 kDa, consisting of PIF1, -2, and -3. This revised the previous knowledge that the core complex was about 170 kDa and contained PIF1 to -4. Analysis of the PIF complex in cellular fractions suggested that it is assembled in the cytoplasm before being transported to the nucleus and subsequently incorporated into the envelopes of ODVs. Only the full complex, not the subcomplex, is resistant to proteolytic attack, indicating the essentiality of correct complex assembly for oral infection. IMPORTANCE Entry of baculovirus into host insects is mediated by a per os infectivity factor (PIF) complex on the envelopes of occlusion-derived viruses (ODVs). Knowledge of the composition and structure of the PIF complex is fundamental to understanding its mode of action. By using multiple approaches, we determined the complete list of proteins (nine) in the PIF complex. In contrast to previous knowledge in the field, the core complex is revised to ∼230 kDa and consists of PIF1 to -3 but not PIF4. Interestingly, our results suggest that the PIF complex is formed in the cytoplasm prior to its transport to the nucleus and subsequent incorporation into ODVs. Only the full complex is resistant to proteolytic degradation in the insect midgut, implying the critical role of the entire complex. These findings provide the baseline for future studies on the ODV entry mechanism mediated by the multiprotein complex.

scholarly journals Population Pharmacokinetic Model for Vancomycin Used in Open Heart Surgery: Model-Based Evaluation of Standard Dosing Regimens

2018 ◽  
Vol 62 (7) ◽  
Author(s):  
Saeed A. Alqahtani ◽  
Abdullah S. Alsultan ◽  
Hussain M. Alqattan ◽  
Ahmed Eldemerdash ◽  
Turki B. Albacker
Keyword(s):  
Heart Surgery ◽  
Open Heart Surgery ◽  
Central Compartment ◽  
Volume Of Distribution ◽  
Peripheral Compartment ◽  
Population Pharmacokinetic ◽  
Albumin Concentration ◽  
Open Heart ◽  
Blood Samples ◽  
Dosing Regimens

ABSTRACTThe purpose of this study was to investigate the population pharmacokinetics of vancomycin in patients undergoing open heart surgery. In this observational pharmacokinetic study, multiple blood samples were drawn over a 48-h period of intravenous vancomycin in patients who were undergoing open heart surgery. Blood samples were analyzed using an Architect i4000SR immunoassay analyzer. Population pharmacokinetic models were developed using Monolix 4.4 software. Pharmacokinetic-pharmacodynamic (PK-PD) simulations were performed to explore the ability of different dosage regimens to achieve the pharmacodynamic targets. A total of 168 blood samples were analyzed from 28 patients. The pharmacokinetics of vancomycin are best described by a two-compartment model with between-subject variability in clearance (CL), the volume of distribution of the central compartment (V1), and volume of distribution of the peripheral compartment (V2). The CL and theV1of vancomycin were related to creatinine CL (CLCR), body weight, and albumin concentration. Dosing simulations showed that standard dosing regimens of 1 and 1.5 g failed to achieve the PK-PD target of AUC0–24/MIC > 400 for an MIC of 1 mg/liter, while high weight-based dosing regimens were able to achieve the PK-PD target. In summary, the administration of standard doses of 1 and 1.5 g of vancomycin two times daily provided inadequate antibiotic prophylaxis in patients undergoing open heart surgery. The same findings were obtained when 15- and 20-mg/kg doses of vancomycin were administered. Achieving the PK-PD target required higher doses (25 and 30 mg/kg) of vancomycin.

scholarly journals New Semiphysiological Absorption Model To Assess the Pharmacodynamic Profile of Cefuroxime Axetil Using Nonparametric and Parametric Population Pharmacokinetics

2009 ◽  
Vol 53 (8) ◽  
pp. 3462-3471 ◽  
Author(s):  
J. B. Bulitta ◽  
C. B. Landersdorfer ◽  
M. Kinzig ◽  
U. Holzgrabe ◽  
F. Sorgel
Keyword(s):  
Predictive Performance ◽  
Volume Of Distribution ◽  
Drug Analysis ◽  
Cefuroxime Axetil ◽  
Population Pharmacokinetic ◽  
Susceptibility Data ◽  
Pharmacodynamic Profile ◽  
Population Pk ◽  
Liquid Chromatography Tandem Mass ◽  
Tract Infections

ABSTRACT Cefuroxime axetil is widely used to treat respiratory tract infections. We are not aware of a population pharmacokinetic (PK) model for cefuroxime axetil. Our objectives were to develop a semiphysiological population PK model and evaluate the pharmacodynamic profile for cefuroxime axetil. Twenty-four healthy volunteers received 250 mg oral cefuroxime as a suspension after a standardized breakfast. Liquid chromatography-tandem mass spectrometry was used for drug analysis, NONMEM and S-ADAPT (results reported) were used for parametric population PK modeling, and NPAG was used for nonparametric population PK modeling. Monte Carlo simulations were used to predict the duration for which the non-protein-bound-plasma concentration was above the MIC (fT>MIC). A model with one disposition compartment, a saturable and time-dependent drug release from the stomach, and fast drug absorption from the intestine yielded precise (r > 0.992) and unbiased curve fits and an excellent predictive performance. The apparent clearance was 21.7 liters/h (19.8% coefficient of variation [CV]) and the volume of distribution 38.7 liters (18.3% CV). Robust (≥90%) probabilities of target attainment (PTAs) were achieved by 250 mg cefuroxime given every 12 h (q12h) or q8h for MICs of ≤0.375 mg/liter or ≤0.5 mg/liter, respectively, for the bacteriostasis target fT>MIC of ≥40% and for MICs of ≤0.094 mg/liter or ≤0.375 mg/liter, respectively, for the near-maximal-killing target fT>MIC of ≥65%. For the ≥40% fT>MIC target, the PTAs for 250 mg cefuroxime q12h were ≥97.8% for S treptococcus pyogenes and penicillin-susceptible S treptococcus pneumoniae. Cefuroxime at 250 mg q12h or q8h achieved PTAs below 73% or 92%, respectively, for H aemophilus influenzae, M oraxella catarrhalis, and penicillin-intermediate S. pneumoniae for susceptibility data from various countries. Depending on the MIC distribution, 250 mg oral cefuroxime q8h instead of q12h should be considered, especially for more-severe infections that require near-maximal killing by cefuroxime.

scholarly journals Population Pharmacokinetics of Tafenoquine, a Novel Antimalarial

2018 ◽  
Vol 62 (11) ◽  
Author(s):  
Nilay Thakkar ◽  
Justin A. Green ◽  
Gavin C. K. W. Koh ◽  
Stephan Duparc ◽  
David Tenero ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Studies ◽  
Apparent Volume ◽  
Volume Of Distribution ◽  
Population Pharmacokinetic ◽  
Radical Cure ◽  
Phase 3 ◽  
Content Type ◽  
Clinical Trial Simulations ◽  
Apparent Volume Of Distribution

ABSTRACTTafenoquine is a novel 8-aminoquinoline antimalarial drug recently approved by the U.S. Food and Drug Administration (FDA) for the radical cure of acutePlasmodium vivaxmalaria, which is the first new treatment in almost 60 years. A population pharmacokinetic (POP PK) analysis was conducted with tafenoquine exposure data obtained following oral administration from 6 clinical studies in phase 1 through phase 3 with a nonlinear mixed effects modeling approach. The impacts of patient demographics, baseline characteristics, and extrinsic factors, such as formulation, were evaluated. Model performance was assessed using techniques such as bootstrapping, visual predictive checks, and external data validation from a phase 3 study not used in model fitting and parameter estimation. Based on the analysis, the systemic pharmacokinetics of tafenoquine were adequately described using a two-compartment model. The final POP PK model included body weight (allometric scaling) on apparent oral and intercompartmental clearance (CL/FandQ/F, respectively), apparent volume of distribution for central and peripheral compartments (V2/FandV3/F, respectively), formulation on systemic bioavailability (F1) and absorption rate constant (Ka), and health status on apparent volume of distribution. The key tafenoquine population parameter estimates were 2.96 liters/h for CL/Fand 915 liters forV2/FinP. vivax-infected subjects. Additionally, the analyses demonstrated no clinically relevant difference in relative bioavailability across the capsule and tablet formulations administered in these clinical studies. In conclusion, a POP PK model for tafenoquine was developed. Clinical trial simulations based on this model supported bridging the exposures across two different formulations. This POP PK model can be applied to aid and perform clinical trial simulations in other scenarios and populations, such as pediatric populations.

scholarly journals Age, Weight, and CYP2D6 Genotype Are Major Determinants of Primaquine Pharmacokinetics in African Children

2017 ◽  
Vol 61 (5) ◽  
Author(s):  
Bronner P. Gonçalves ◽  
Helmi Pett ◽  
Alfred B. Tiono ◽  
Daryl Murry ◽  
Sodiomon B. Sirima ◽  
...  
Keyword(s):  
Parent Compound ◽  
Age Groups ◽  
Artemisinin Resistance ◽  
Community Treatment ◽  
Population Pharmacokinetic ◽  
Cyp2d6 Genotype ◽  
Content Type ◽  
Population Pharmacokinetic Modeling ◽  
African Children ◽  
The Impact

ABSTRACT Low-dose primaquine is recommended to prevent Plasmodium falciparum malaria transmission in areas threatened by artemisinin resistance and areas aiming for malaria elimination. Community treatment campaigns with artemisinin-based combination therapy in combination with the gametocytocidal primaquine dose target all age groups, but no studies thus far have assessed the pharmacokinetics of this gametocytocidal drug in African children. We recruited 40 children participating in a primaquine efficacy trial in Burkina Faso to study primaquine pharmacokinetics. These children received artemether-lumefantrine and either a 0.25- or a 0.40-mg/kg primaquine dose. Seven blood samples were collected from each participant for primaquine and carboxy-primaquine plasma levels determinations: one sample was collected before primaquine administration and six after primaquine administration according to partially overlapping sampling schedules. Physiological population pharmacokinetic modeling was used to assess the impact of weight, age, and CYP2D6 genotype on primaquine and carboxy-primaquine pharmacokinetics. Despite linear weight normalized dosing, the areas under the plasma concentration-time curves and the peak concentrations for both primaquine and carboxy-primaquine increased with age and body weight. Children who were CYP2D6 poor metabolizers had higher levels of the parent compound, indicating a lower primaquine CYP2D6-mediated metabolism. Our data indicate that primaquine and carboxy-primaquine pharmacokinetics are influenced by age, weight, and CYP2D6 genotype and suggest that dosing strategies may have to be reconsidered to maximize the transmission-blocking properties of primaquine. (This study has been registered at ClinicalTrials.gov under registration no. NCT01935882.)

scholarly journals Differences in the Pharmacokinetics of Gentamicin between Oncology and Nononcology Pediatric Patients

2019 ◽  
Vol 64 (2) ◽  
Author(s):  
C. C. Llanos-Paez ◽  
C. E. Staatz ◽  
R. Lawson ◽  
S. Hennig
Keyword(s):  
Fat Mass ◽  
Pediatric Patients ◽  
Drug Disposition ◽  
Therapeutic Index ◽  
Volume Of Distribution ◽  
Population Pharmacokinetic ◽  
Time Curve ◽  
Exposure Target ◽  
Low Exposure ◽  
The Impact

ABSTRACT Dosing gentamicin in pediatric patients can be difficult due to its narrow therapeutic index. A significantly higher percentage of fat mass has been observed in children receiving oncology treatment than in those who are not. Differences in the pharmacokinetics of gentamicin between oncology and nononcology pediatric patients and individual dosage requirements were evaluated in this study, using normal fat mass (NFM) as a body size descriptor. Data from 423 oncology and 115 nononcology patients were analyzed. Differences in drug disposition were observed between the oncology and nononcology patients, with oncology patients having a 15% lower central volume of distribution and 32% lower intercompartmental clearance. Simulations based on the population pharmacokinetic model demonstrated low exposure target attainment in all individuals at the current clinical recommended starting dose of 7.5 mg/kg of body weight once daily, with 57.4% of oncology and 35.7% of nononcology subjects achieving a peak concentration (Cmax) of ≥25 mg/liter and 64.3% of oncology and 65.6% of nononcology subjects achieving an area under the concentration-time curve at 24 h postdose (AUC24) of ≥70 mg · h/liter after the first dose. Based on simulations, the extent of the impact of differences in drug disposition between the two cohorts appeared to be dependent on the exposure target under examination. Greater differences in achieving a Cmax target of >25 mg/liter than an AUC24 target of ≥70 mg · h/liter between the cohorts was observed. Further investigation into whether differences in the pharmacokinetics of gentamicin between oncology and nononcology patients are a consequence of changes in body composition is required.

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