Population Pharmacokinetics and Pharmacodynamics of Doripenem in Obese, Hospitalized Patients

Background: Doripenem population pharmacokinetics and dosing recommendations are limited in obesity. Objective: To evaluate the population pharmacokinetics and pharmacodynamics of doripenem in obese patients. Methods: Hospitalized adults with a body mass index (BMI) ≥ 40 kg/m2 or total body weight (TBW) ≥45.5 kg over their ideal body weight received doripenem 500 mg every 8 hours, infused over 1 hour. Population pharmacokinetic analyses were performed using NONMEM, and Monte Carlo simulations were performed for 5 intermittent and prolonged infusion dosing regimens to calculate probability of target attainment (PTA) at 40% and 100% fT>MIC (free drug concentrations above the minimum inhibitory concentration). Results: A total of 20 patients were studied: 10 in an intensive care unit (ICU) and 10 in a non-ICU. A 2-compartment model with first-order elimination best described the serum concentration-time data. Doripenem clearance (CL) was significantly associated with creatinine CL (CRCL), volume of the central compartment with TBW and ICU residence, and volume of the peripheral compartment with TBW ( P < 0.05). Using 40% fT>MIC, PTA was >90% for all simulated dosing regimens at MICs ≤2 mg/L. Using 100% fT>MIC, prolonged infusions of 1 g every 6 hours and 2 g every 8 hours achieved >90% PTA at MICs ≤2 mg/L. Conclusions: CRCL, ICU residence, and TBW are significantly associated with doripenem pharmacokinetics. Currently approved dosing regimens provide adequate pharmacodynamic exposures at 40% fT>MIC for susceptible bacteria in obese patients. However, prolonged infusions of larger doses are needed if a higher pharmacodynamic target is desired.

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Population Pharmacokinetics and Pharmacodynamics of Meropenem in Nonobese, Obese, and Morbidly Obese Patients

The Journal of Clinical Pharmacology ◽

10.1002/jcph.812 ◽

2016 ◽

Vol 57 (3) ◽

pp. 356-368 ◽

Cited By ~ 10

Author(s):

Eun Kyoung Chung ◽

S. Christian Cheatham ◽

Megan R. Fleming ◽

Daniel P. Healy ◽

Michael B. Kays

Keyword(s):

Population Pharmacokinetics ◽

Morbidly Obese ◽

Obese Patients ◽

Pharmacokinetics And Pharmacodynamics ◽

Population Pharmacokinetics And Pharmacodynamics

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Population Pharmacokinetics and Pharmacodynamics of Extended-Infusion Piperacillin and Tazobactam in Critically Ill Children

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02089-15 ◽

2015 ◽

Vol 60 (1) ◽

pp. 522-531 ◽

Cited By ~ 18

Author(s):

Kristen Nichols ◽

Eun Kyoung Chung ◽

Chad A. Knoderer ◽

Lauren E. Buenger ◽

Daniel P. Healy ◽

...

Keyword(s):

Steady State ◽

Population Pharmacokinetics ◽

Critically Ill ◽

Critically Ill Children ◽

Population Pharmacokinetic ◽

Pharmacokinetic Data ◽

Pharmacokinetics And Pharmacodynamics ◽

Study Objective ◽

Population Pharmacokinetics And Pharmacodynamics ◽

Extended Infusion

ABSTRACTThe study objective was to evaluate the population pharmacokinetics and pharmacodynamics of extended-infusion piperacillin-tazobactam in children hospitalized in an intensive care unit. Seventy-two serum samples were collected at steady state from 12 patients who received piperacillin-tazobactam at 100/12.5 mg/kg of body weight every 8 h infused over 4 h. Population pharmacokinetic analyses were performed using NONMEM, and Monte Carlo simulations were performed to estimate the piperacillin pharmacokinetic profiles for dosing regimens of 80 to 100 mg/kg of the piperacillin component given every 6 to 8 h and infused over 0.5, 3, or 4 h. The probability of target attainment (PTA) for a cumulative percentage of the dosing interval that the drug concentration exceeds the MIC under steady-state pharmacokinetic conditions (TMIC) of ≥50% was calculated at MICs ranging from 0.25 to 64 mg/liter. The mean ± standard deviation (SD) age, weight, and estimated glomerular filtration rate were 5 ± 3 years, 17 ± 6.2 kg, and 118 ± 41 ml/min/1.73 m2, respectively. A one-compartment model with zero-order input and first-order elimination best fit the pharmacokinetic data for both drugs. Weight was significantly associated with piperacillin clearance, and weight and sex were significantly associated with tazobactam clearance. Pharmacokinetic parameters (mean ± SD) for piperacillin and tazobactam were as follows: clearance, 0.22 ± 0.07 and 0.19 ± 0.07 liter/h/kg, respectively; volume of distribution, 0.43 ± 0.16 and 0.37 ± 0.14 liter/kg, respectively. All extended-infusion regimens achieved PTAs of >90% at MICs of ≤16 mg/liter. Only the 3-h infusion regimens given every 6 h achieved PTAs of >90% at an MIC of 32 mg/liter. For susceptible bacterial pathogens, piperacillin-tazobactam doses of ≥80/10 mg/kg given every 8 h and infused over 4 h achieve adequate pharmacodynamic exposures in critically ill children.

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Population Pharmacokinetics and Pharmacodynamics of Artemether and Lumefantrine during Combination Treatment in Children with Uncomplicated Falciparum Malaria in Tanzania

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00252-10 ◽

2010 ◽

Vol 54 (11) ◽

pp. 4780-4788 ◽

Cited By ~ 41

Author(s):

Sofia Friberg Hietala ◽

Andreas Mårtensson ◽

Billy Ngasala ◽

Sabina Dahlström ◽

Niklas Lindegårdh ◽

...

Keyword(s):

Population Pharmacokinetics ◽

Falciparum Malaria ◽

Compartment Model ◽

Uncomplicated Falciparum Malaria ◽

Oral Clearance ◽

Pharmacokinetics And Pharmacodynamics ◽

Population Pharmacokinetics And Pharmacodynamics ◽

Drug Concentrations ◽

Rough Approximation ◽

Parasite Dynamics

ABSTRACT The combination of artemether (ARM) and lumefantrine is currently the first-line treatment of uncomplicated falciparum malaria in mainland Tanzania. While the exposure to lumefantrine has been associated with the probability of adequate clinical and parasitological cure, increasing exposure to artemether and the active metabolite dihydroartemisinin (DHA) has been shown to decrease the parasite clearance time. The aim of this analysis was to describe the pharmacokinetics and pharmacodynamics of artemether, dihydroartemisinin, and lumefantrine in African children with uncomplicated malaria. In addition to drug concentrations and parasitemias from 50 Tanzanian children with falciparum malaria, peripheral parasite densities from 11 asymptomatic children were included in the model of the parasite dynamics. The population pharmacokinetics and pharmacodynamics of artemether, dihydroartemisinin, and lumefantrine were modeled in NONMEM. The distribution of artemether was described by a two-compartment model with a rapid absorption and elimination through metabolism to dihydroartemisinin. Dihydroartemisinin concentrations were adequately illustrated by a one-compartment model. The pharmacokinetics of artemether was time dependent, with typical oral clearance increasing from 2.6 liters/h/kg on day 1 to 10 liters/h/kg on day 3. The pharmacokinetics of lumefantrine was sufficiently described by a one-compartment model with an absorption lag time. The typical value of oral clearance was estimated to 77 ml/h/kg. The proposed semimechanistic model of parasite dynamics, while a rough approximation of the complex interplay between malaria parasite and the human host, adequately described the early effect of ARM and DHA concentrations on the parasite density in malaria patients. However, the poor precision in some parameters illustrates the need for further data to support and refine this model.

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Population Pharmacokinetics of Arbekacin in Patients Infected with Methicillin-Resistant Staphylococcus aureus

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00420-05 ◽

2006 ◽

Vol 50 (11) ◽

pp. 3754-3762 ◽

Cited By ~ 26

Author(s):

Yusuke Tanigawara ◽

Reiko Sato ◽

Kunihiko Morita ◽

Mitsuo Kaku ◽

Naoki Aikawa ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Population Pharmacokinetics ◽

Elderly Subjects ◽

Pharmacokinetic Analysis ◽

Pharmacokinetic Parameters ◽

Peripheral Compartment ◽

Population Pharmacokinetic ◽

Time Data ◽

Mixed Effect ◽

Methicillin Resistant

ABSTRACT Arbekacin, a derivative of dibekacin, is an aminoglycoside developed and widely used in Japan for the treatment of patients infected with methicillin-resistant Staphylococcus aureus (MRSA). The population pharmacokinetics of arbekacin was investigated in the Japanese, using 353 patients infected with MRSA and 50 healthy or renally impaired volunteers. The age of the study population ranged from 8 to 95 years, and weight ranged from 10.8 to 107 kg. In total, 1,581 serum arbekacin concentrations were measured (primarily from routine patient care) and used to perform the present pharmacokinetic analysis. Drug concentration-time data were well described by a two-compartment open model. Factors influencing arbekacin pharmacokinetics were investigated using a nonlinear mixed-effect model analysis. The best-developed model showed that drug clearance (CL) was related to creatinine clearance (CLCR), age, and body weight (WT), as expressed by CL (liter/h) = 0.0319CLCR + (26.5/age) (CLCR < 80 ml/min) and CL (liter/h) = 0.0130 CLCR + 0.0342WT + (26.5/age) (CLCR ≥ 80 ml/min). The volume of distribution for the central and peripheral compartments was different in healthy subjects and infected patients, and this difference was more pronounced among disease types. The elderly subjects (aged 80 years or over) exhibited, on average, a 19% greater volume for the central compartment. The volumes for the peripheral compartment were 50.6 liters in patients with pneumonia and 24.3 liters in patients with sepsis. The population pharmacokinetic parameters of arbekacin obtained here are useful for optimal use of this aminoglycoside in the treatment of MRSA-infected patients.

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Population Pharmacokinetics of Acyclovir in Children and Young People with Malignancy after Administration of Intravenous Acyclovir or Oral Valacyclovir

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01138-08 ◽

2009 ◽

Vol 53 (7) ◽

pp. 2918-2927 ◽

Cited By ~ 11

Author(s):

L. Zeng ◽

C. E. Nath ◽

E. Y. L. Blair ◽

P. J. Shaw ◽

K. Stephen ◽

...

Keyword(s):

Body Weight ◽

Young People ◽

Population Pharmacokinetics ◽

Pharmacokinetic Model ◽

Population Pharmacokinetic ◽

Time Data ◽

Mixed Effect ◽

Varicella Zoster ◽

Concentration Time ◽

Intravenous Acyclovir

ABSTRACT Acyclovir is effective in the prevention and treatment of herpes simplex virus (HSV) and varicella-zoster virus (VZV) infections. The aim of this study was to characterize the population pharmacokinetics of acyclovir observed following treatment with intravenous acyclovir and oral valacyclovir (valaciclovir) in young people with malignancy. Plasma acyclovir concentration-time data were collected from 43 patients (age range, 9 months to 20 years) who had been given multiple doses of acyclovir (5 mg/kg of body weight) and/or valacyclovir (10 mg/kg). Nonlinear mixed-effect modeling was employed to analyze acyclovir population pharmacokinetics and identify influential covariates. Simulations (n = 1,000) were conducted to explore the ability of the current doses to maintain acyclovir concentrations above the recommended 50% inhibitory concentration for HSV or VZV (0.56 mg/liter or 1.125 mg/liter, respectively) for more than 12 h. A one-compartment pharmacokinetic model with first-order elimination best described the acyclovir concentration-time data. The population mean estimates for clearance (CL), volume of distribution (V), absorption rate (ka ), and bioavailability (F) were 3.55 liters/h, 7.36 liters, 0.63 h−1, and 0.60, respectively. Inclusion of body weight and estimated creatinine CL (CLCR) in the final model reduced the interindividual variabilities in CL and V from 61% to 24% and from 75% to 36%, respectively. Simulations revealed that with the use of the current doses, maximal efficacy can be achieved in over 45% of patients weighing 25 to 50 kg and with CLCR levels of 2.0 to 4.0 liters/h/m2, but only in a much smaller proportion of patients, with low weights (10 kg) and high CLCRs (5.5 liters/h/m2), suggesting that higher doses are required for this subgroup. This validated population pharmacokinetic model for acyclovir may be used to develop dosing guidelines for safe and effective antiviral therapy in young people with malignancy.

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