Population Pharmacokinetics of Emtricitabine in HIV-1-Infected Adult Patients

The aims of this study were to describe emtricitabine concentration-time courses in a large population of HIV-1-infected adults, to evaluate the influence of renal function on emtricitabine disposition, and to assess current dosing adjustment recommendations. Emtricitabine blood plasma concentrations were determined from samples collected from 161 adult patients during therapeutic drug monitoring and measured by liquid chromatography coupled to tandem mass spectrometry. The data were analyzed by a population approach. Emtricitabine pharmacokinetics was best described by a two-compartment model in which the absorption and distribution rate constants were assumed to be equal. Typical population parameter estimates (interindividual variability) were apparent elimination and intercompartmental clearances of 15.1 liters/h (17.4%) and 5.75 liters/h, respectively, and apparent central and peripheral volumes of distribution of 42.3 liters and 55.4 liters, respectively. The apparent elimination clearance was significantly related to creatinine clearance (CL_CR), reflecting renal function. For 200 mg once a day (QD), the median area under the concentration-time curve over 24 h (AUC_0-24) was 12.5 mg · h/liter for patients with normal renal function (CL_CR, >80 ml/min), 14.7 mg · h/liter for patients with mild renal impairment (CL_CR, 79 to 50 ml/min), and 17.9 mg · h/liter for patients with moderate renal impairment (CL_CR, 49 to 30 ml/min). Simulations of the recommended dosing schemes for the oral solid form of emtricitabine (i.e., 200 mg per 48 h according to renal function) led to lower emtricitabine exposures for patients with moderate renal impairment (median AUC_0-48, 17.2 mg · h/liter) than for patients with normal renal function (median AUC_0-48, 25.6 mg · h/liter). Administering 18 ml of emtricitabine oral solution (10 mg/ml) QD to patients with moderate renal impairment should yield emtricitabine exposures similar to those in patients with normal renal function.     

Pharmacokinetics and Pharmacodynamics of Continuous-Infusion Meropenem in Pediatric Hematopoietic Stem Cell Transplant Patients

This study explored the pharmacokinetics and the pharmacodynamics of continuous-infusion meropenem in a population of pediatric hematopoietic stem cell transplant (HSCT) patients who underwent therapeutic drug monitoring. The relationship between meropenem clearance (CL_M) and estimated creatinine clearance (CL_CR) was assessed by nonlinear regression. A Monte Carlo simulation was performed to investigate the predictive performance of five dosing regimens (15 to 90 mg/kg of body weight/day) for the empirical treatment of severe Gram-negative-related infections in relation to four different categories of renal function. The optimal target was defined as a probability of target attainment (PTA) of ≥90% at steady-state concentration-to-MIC ratios (C_SS/MIC) of ≥1 and ≥4 for MICs of up to 8 mg/liter. A total of 21 patients with 44 meropenem C_SS were included. A good relationship between CL_M and estimated CL_CR was observed (r² = 0.733). Simulations showed that at an MIC of 2 mg/liter, the administration of continuous-infusion meropenem at doses of 15, 30, 45, and 60 mg/kg/day may achieve a PTA of ≥90% at a C_SS/MIC ratio of ≥4 in the CL_CR categories of 40 to <80, 80 to <120, 120 to <200, and 200 to <300 ml/min/1.73 m², respectively. At an MIC of 8 mg/liter, doses of up to 90 mg/kg/day by continuous infusion may achieve optimal PTA only in the CL_CR categories of 40 to <80 and 80 to <120 ml/min/1.73 m². Continuous-infusion meropenem at dosages up to 90 mg/kg/day might be effective for optimal treatment of severe Gram-negative-related infections in pediatric HSCT patients, even when caused by carbapenem-resistant pathogens with an MIC of up to 8 mg/liter.     

Safety,Tolerability, and Pharmacokinetics of Ribavirin in Hepatitis C Virus-Infected Patients with Various Degrees of Renal Impairment

Ribavirin (RBV) is an integral part of standard-of-care hepatitis C virus (HCV) treatments and many future regimens under investigation. The pharmacokinetics (PK), safety, and tolerability of RBV in chronically HCV-infected patients with renal impairment are not well defined and were the focus of an open-label PK study in HCV-infected patients receiving RBV plus pegylated interferon. Serial RBV plasma samples were collected over 12 h on day 1 of weeks 1 and 12 from patients with moderate renal impairment (creatinine clearance [CL_CR], 30 to 50 ml/min; RBV, 600 mg daily), severe renal impairment (CL_CR, <30 ml/min; RBV, 400 mg daily), end-stage renal disease (ESRD) (RBV, 200 mg daily), or normal renal function (CL_CR, >80 ml/min; RBV, 800 to 1,200 mg daily). Of the 44 patients, 9 had moderately impaired renal function, 10 had severely impaired renal function, 13 had ESRD, and 12 had normal renal function. The RBV dose was reduced because of adverse events (AEs) in 71% and 53% of severe and moderate renal impairment groups, respectively. Despite this modification, patients with moderate and severe impairment had 12-hour (area under the concentration-time curve from 0 to 12 h [AUC_0–12]) values 36% (38,452 ng · h/ml) and 25% (35,101 ng · h/ml) higher, respectively, than those with normal renal function (28,192 ng · h/ml). Patients with ESRD tolerated a 200-mg daily dose, and AUC_0–12 was 20% lower (22,629 ng · h/ml) than in patients with normal renal function. PK modeling and simulation (M&S) indicated that doses of 200 mg or 400 mg alternating daily for patients with moderate renal impairment and 200 mg daily for patients with severe renal impairment were the most appropriate dose regimens in these patients.     

Identification of Optimal Renal Dosage Adjustments for Traditional and Extended-Infusion Piperacillin-Tazobactam Dosing Regimens in Hospitalized Patients

This study examined the effect of various levels of renal impairment on the probability of achieving free drug concentrations that exceed the MIC for 50% of the dosing interval (50% fT > MIC) for traditional and extended-infusion piperacillin-tazobactam (TZP) dosing strategies. It also identified optimal renal dosage adjustments for traditional and extended-infusion dosing schemes that yielded probability of target attainment (PTA) and exposure profiles that were isometric to those of the parent regimens. Data from 105 patients were analyzed using the population pharmacokinetic modeling program BigNPAG. To assess the effect of creatinine clearance (CL_CR) on overall clearance, TZP clearance was made proportional to the estimated CL_CR. A Monte Carlo simulation (9,999 subjects) was performed for the traditional dosing scheme (4.5 g infused during 30 min every 6 h) and the extended-infusion TZP dosing scheme (3.375 g infused during 4 h every 8 h). The fraction of simulated subjects who achieved 50% fT > MIC was calculated for the range of piperacillin MICs from 0.25 to 32 mg/liter and stratified by CL_CR. The traditional TZP regimen displayed the greatest variability in PTA across MIC values, especially for MIC values exceeding 4 mg/liter, when stratified by CL_CR. In contrast, the PTA for the extended-infusion TZP regimen exceeded ≥80% for MIC values of ≤8 mg/liter across all CL_CR strata. All regimens were associated with suboptimal PTA for MIC values of ≥32 mg/liter irrespective of the CL_CR. The CL_CR adjustments for traditional and extended-infusion TZP dosing regimens should be considered at a CL_CR of ≤20 ml/min.Piperacillin-tazobactam (TZP), a combination product of a semisynthetic penicillin and a beta-lactamase inhibitor, exhibits broad-spectrum activity and low toxicity, and it is indicated for a variety of clinical infections (1). TZP is excreted primarily from the body via the kidney, with the majority (∼70%) being eliminated as unchanged drug in the urine (1). Because TZP is eliminated primarily by the kidneys, dose alterations are required for patients with renal impairment.Despite 15 years of clinical experience, the effect of renal impairment on the pharmacodynamic profile of TZP has not been well evaluated. It is well known that beta-lactam drugs such as TZP exert bactericidal activity in a time-dependent manner, with the time the free drug concentrations exceed the MIC during the dosing interval (fT > MIC) being the key pharmacodynamic parameter (4, 6, 7, 11, 12, 22, 27, 29). For beta-lactams like TZP, it appears that bactericidal activity is optimized when fT > MIC exceeds 50% of the dosing interval (designated 50% fT > MIC) (8, 10). Among the studies that have characterized the ability of various TZP dosing strategies to achieve 50% fT > MIC (13, 17, 24), all have reported the overall probability of target attainment (PTA); we are unaware of any previous study that stratified PTA by renal function. Additionally, no study has assessed the effect of renal dose adjustments on the ability to achieve the desired pharmacodynamic target. An understanding of the effects of renal impairment and renal dose adjustment schemes on the pharmacodynamic profile are clinically important, because the majority of patients receiving TZP have some degree of renal impairment and often are administered a TZP regimen that is adjusted accordingly. While effectiveness is often the primary interest, minimizing TZP accumulation or excessive exposure also is of great importance. In the presence of renal dysfunction, TZP accumulation may occur and result in unnecessary toxicity. Quantifying the degree of TZP accumulation that results from diminished renal function will assist in identifying the creatinine clearance (CL_CR) breakpoint and dose adjustment that would leave the PTA substantially unaltered and still not result in profound accumulation.This study had two specific aims. First, we examined the effect of various levels of renal impairment on the probability of achieving 50% fT > MIC for traditional and extended-infusion TZP dosing strategies. Second, we sought to identify renal dosage adjustments for traditional and extended-infusion dosing schemes that yielded PTA and exposure profiles for the TZP renal dosing strategies that were isometric to parent regimens. For the purpose of the analysis, we characterized only the pharmacodynamic profile of piperacillin. We did not examine the pharmacodynamic profile of tazobactam, because current doses of tazobactam in the TZP formulation have been shown to be sufficient for an antibacterial effect when the target is attaining a free-drug concentration exceeding the MIC for 50% of the dosing interval (26).     

Population Pharmacokinetics of Doripenem in Critically Ill Patients with Sepsis in a Malaysian Intensive Care Unit

Doripenem has been recently introduced in Malaysia and is used for severe infections in the intensive care unit. However, limited data currently exist to guide optimal dosing in this scenario. We aimed to describe the population pharmacokinetics of doripenem in Malaysian critically ill patients with sepsis and use Monte Carlo dosing simulations to develop clinically relevant dosing guidelines for these patients. In this pharmacokinetic study, 12 critically ill adult patients with sepsis receiving 500 mg of doripenem every 8 h as a 1-hour infusion were enrolled. Serial blood samples were collected on 2 different days, and population pharmacokinetic analysis was performed using a nonlinear mixed-effects modeling approach. A two-compartment linear model with between-subject and between-occasion variability on clearance was adequate in describing the data. The typical volume of distribution and clearance of doripenem in this cohort were 0.47 liters/kg and 0.14 liters/kg/h, respectively. Doripenem clearance was significantly influenced by patients'' creatinine clearance (CL_CR), such that a 30-ml/min increase in the estimated CL_CR would increase doripenem CL by 52%. Monte Carlo dosing simulations suggested that, for pathogens with a MIC of 8 mg/liter, a dose of 1,000 mg every 8 h as a 4-h infusion is optimal for patients with a CL_CR of 30 to 100 ml/min, while a dose of 2,000 mg every 8 h as a 4-h infusion is best for patients manifesting a CL_CR of >100 ml/min. Findings from this study suggest that, for doripenem usage in Malaysian critically ill patients, an alternative dosing approach may be meritorious, particularly when multidrug resistance pathogens are involved.     

Evaluation of Several Dosing Regimens of Cefepime, with Various Simulations of Renal Function, against Clinical Isolates of Pseudomonas aeruginosa in a Pharmacodynamic Infection Model

The objectives of this study were as follows: (i) to examine the killing activity of 2-g doses of cefepime against two clinical isolates (mucoid and nonmucoid) of Pseudomonas aeruginosa in a pharmacodynamic in vitro infection model, (ii) to compare the percentage of time above the MIC (T > MIC) for each of the regimens against P. aeruginosa, and (iii) to evaluate the area under the bactericidal curve for each regimen. Cefepime was administered at intervals of 8, 12, and 24 h with and without tobramycin, and two different levels of renal function were simulated: normal (creatinine clearance [CL_CR] = 90 ml/min) and decreased (CR_CL = 60 ml/min). Also, the killing activity of cefepime with and without tobramycin was compared to the killing activity of ceftazidime (2 g every 8 h) with and without tobramycin. The T > MIC was 100% in the central chamber except for the regimen in which cefepime was administered every 12 h and the CL_CR was 90 ml/min, which provided concentrations above the MIC for 92% of the dosing interval against the C31 (mucoid; MIC of cefepime, 4 μg/ml) isolate and for 75% of the interval against the C34 (nonmucoid; MIC of cefepime, 8 μg/ml) isolate. All cefepime and ceftazidime monotherapy simulations resulted in 99.9% killing of the nonmucoid isolate within 4 to 8 h and within 4 to 6 h, respectively. Against the mucoid isolate, 99.9% killing was achieved only with combination therapy. The results of this study indicate that cefepime dosed at 2 g every 12 h under conditions of normal renal function and every 24 h with decreased creatinine clearance (60 ml/min) is effective both as monotherapy and in combination therapy against a nonmucoid strain of P. aeruginosa. With cefepime MICs of 4 and 8 μg/ml, the single-agent regimens provided T > MIC values in the central chamber for 92 and ≥75% of the dosing interval against the mucoid and nonmucoid isolates, respectively. Cefepime dosed at 2 g every 12 h, with a creatinine clearance of 90 ml/min, and every 24 h, with a creatinine clearance of 60 ml/min, resulted in killing activity equivalent to that of ceftazidime dosed at 2 g every 8 h. None of the monotherapies provided adequate killing of the mucoid strain of P. aeruginosa despite drug concentrations being above the MIC for ≥92% of all dosing intervals. Finally, combination therapy with tobramycin and either cefepime or ceftazidime enhanced the killing of both the mucoid and nonmucoid P. aeruginosa isolates.     

Are standard doses of piperacillin sufficient for critically ill patients with augmented creatinine clearance?

IntroductionThe aim of this study was to explore the impact of augmented creatinine clearance and differing minimum inhibitory concentrations (MIC) on piperacillin pharmacokinetic/pharmacodynamic (PK/PD) target attainment (time above MIC (fT_>MIC)) in critically ill patients with sepsis receiving intermittent dosing.MethodsTo be eligible for enrolment, critically ill patients with sepsis had to be receiving piperacillin-tazobactam 4.5 g intravenously (IV) by intermittent infusion every 6 hours for presumed or confirmed nosocomial infection without significant renal impairment (defined by a plasma creatinine concentration greater than 171 μmol/L or the need for renal replacement therapy). Over a single dosing interval, blood samples were drawn to determine unbound plasma piperacillin concentrations. Renal function was assessed by measuring creatinine clearance (CL_CR). A population PK model was constructed, and the probability of target attainment (PTA) for 50% and 100% fT_>MIC was calculated for varying MIC and CL_CR values.ResultsIn total, 48 patients provided data. Increasing CL_CR values were associated with lower trough plasma piperacillin concentrations (P < 0.01), such that with an MIC of 16 mg/L, 100% fT_>MIC would be achieved in only one-third (n = 16) of patients. Mean piperacillin clearance was approximately 1.5-fold higher than in healthy volunteers and correlated with CL_CR (r = 0.58, P < 0.01). A reduced PTA for all MIC values, when targeting either 50% or 100% fT_>MIC, was noted with increasing CL_CR measures.ConclusionsStandard intermittent piperacillin-tazobactam dosing is unlikely to achieve optimal piperacillin exposures in a significant proportion of critically ill patients with sepsis, owing to elevated drug clearance. These data suggest that CL_CR can be employed as a useful tool to determine whether piperacillin PK/PD target attainment is likely with a range of MIC values.     

Towards Rational Dosing Algorithms for Vancomycin in Neonates and Infants Based on Population Pharmacokinetic Modeling

Because of the recent awareness that vancomycin doses should aim to meet a target area under the concentration-time curve (AUC) instead of trough concentrations, more aggressive dosing regimens are warranted also in the pediatric population. In this study, both neonatal and pediatric pharmacokinetic models for vancomycin were externally evaluated and subsequently used to derive model-based dosing algorithms for neonates, infants, and children. For the external validation, predictions from previously published pharmacokinetic models were compared to new data. Simulations were performed in order to evaluate current dosing regimens and to propose a model-based dosing algorithm. The AUC/MIC over 24 h (AUC₂₄/MIC) was evaluated for all investigated dosing schedules (target of >400), without any concentration exceeding 40 mg/liter. Both the neonatal and pediatric models of vancomycin performed well in the external data sets, resulting in concentrations that were predicted correctly and without bias. For neonates, a dosing algorithm based on body weight at birth and postnatal age is proposed, with daily doses divided over three to four doses. For infants aged <1 year, doses between 32 and 60 mg/kg/day over four doses are proposed, while above 1 year of age, 60 mg/kg/day seems appropriate. As the time to reach steady-state concentrations varies from 155 h in preterm infants to 36 h in children aged >1 year, an initial loading dose is proposed. Based on the externally validated neonatal and pediatric vancomycin models, novel dosing algorithms are proposed for neonates and children aged <1 year. For children aged 1 year and older, the currently advised maintenance dose of 60 mg/kg/day seems appropriate.     

Are ciprofloxacin dosage regimens adequate for antimicrobial efficacy and prevention of resistance? Pseudomonas aeruginosa bloodstream infection in elderly patients as a simulation case study

The aim of this work was to define the optimal dosage (OD) of ciprofloxacin in order to prevent the emergence of bacterial resistance of Pseudomonas aeruginosa in a geriatric population with a bloodstream infection. A thousand pharmacokinetic profiles were simulated with a ciprofloxacin pharmacokinetic model from the literature. Three dosing regimens were tested for five days: once daily (QD), twice daily (BID), and thrice daily (TID). First of all, effective dosages (ED) of ciprofloxacin were defined as those achieving a target AUC₂₄/MIC ≥ 125. Then, these ED were simulated in order to calculate the percentage of time spent within the mutant selection window (T_MSW) and to select optimal dosage (OD) defined as those achieving T_MSW ≤ 20%. Based on the AUC₂₄/MIC, for low MICs (0.125 μg/mL), all dosing regimens recommended by French guidelines were effective. For intermediate MICs (0.25 and 0.5 μg/mL), simulated doses higher than those recommended were needed to achieve the efficacy target. About prevention of resistance for low MICs, dosages recommended were only effective in patients with creatinine clearance (CL_CR) ≥ 60 mL/min. For intermediate MICs, dosages higher than recommended were needed to achieve the optimality target. This study shows that current ciprofloxacin dosing guidelines have not been optimized to prevent the emergence of bacterial resistance, especially in geriatric patients with mild to severe renal impairment. To achieve both efficacy and prevention of resistance, ciprofloxacin dosages greater than those recommended would be needed. Tolerance of such higher doses needs to be evaluated in clinical studies.     

Pharmacokinetics of and short-term virologic response to low-dose 400-milligram once-daily raltegravir maintenance therapy

Because studies showed similar viral suppression with lower raltegravir doses and because Asians usually have high antiretroviral concentrations, we explored low-dose raltegravir therapy in Thais. Nineteen adults on raltegravir at 400 mg twice daily (BID) with HIV RNA loads of <50 copies/ml were randomized to receive 400 mg once daily (QD) or 800 mg QD for 2 weeks, followed by the other dosing for 2 weeks. Intensive pharmacokinetic analyses were performed, and HIV RNA was monitored. Two patients were excluded from the 400-mg QD analysis due to inevaluable pharmacokinetic data. The mean patient weight was 58 kg. Mean pharmacokinetic values were as follows: for raltegravir given at 400 mg BID, the area under the concentration-time curve from 0 to 12 h (AUC_0-12) was 15.6 mg/liter-h and the minimum plasma drug concentration (C_trough) was 0.22 mg/liter; for raltegravir given at 800 mg QD, the AUC_0-24 was 33.6 mg/liter-h and the C_trough was 0.06 mg/liter; and for raltegravir given at 400 mg QD, the AUC_0-24 was 18.6 mg/liter-h and the C_trough was 0.08 mg/liter. The HIV RNA load was <50 copies/ml at each dose level. Compared to the adjusted AUC_0-24 for Westerners on raltegravir at 400 mg BID, Thais on the same dose had double the AUC_0-24 and those on raltegravir at 400 mg QD had a similar AUC_0-24. More patients had a C_trough of <0.021 mg/liter on raltegravir at 400 mg QD (9/17 patients) than on raltegravir at 800 mg QD (1/19 patients) or 400 mg BID (0/19 patients). Seventeen patients used raltegravir at 400 mg QD for a median of 35 weeks; two had confirmed HIV RNA loads between 50 and 200 copies/ml, and both had low C_trough values. Low-dose raltegravir could be a cost-saving option for maintenance therapy in Asians or persons with low body weight. However, raltegravir at 400 mg QD was associated with a low C_trough and with a risk for HIV viremia. Raltegravir at 200 or 300 mg BID should be studied, but new raltegravir formulations will be needed.     

Association between Vancomycin Trough Concentration and Area under the Concentration-Time Curve in Neonates

National treatment guidelines for invasive methicillin-resistant Staphylococcus aureus (MRSA) infections recommend targeting a vancomycin 24-h area under the concentration-time curve (AUC_0–24)-to-MIC ratio of >400. The range of vancomycin trough concentrations that best predicts an AUC_0–24 of >400 in neonates is not known. This understanding would help clarify target trough concentrations in neonates when treating MRSA. A retrospective chart review from a level III neonatal intensive care unit was performed to identify neonates treated with vancomycin over a 5-year period. Vancomycin concentrations and clinical covariates were utilized to develop a one-compartment population pharmacokinetic model and examine the relationships between trough and AUC_0–24 in the study neonates. Monte Carlo simulations were performed to examine the effect of dose, postmenstrual age (PMA), and serum creatinine level on trough and AUC_0–24 achievement. A total of 1,702 vancomycin concentrations from 249 neonates were available for analysis. The median (interquartile range) PMA was 39 weeks (32 to 42 weeks) and weight was 2.9 kg (1.6 to 3.7 kg). Vancomycin clearance was predicted by weight, PMA, and serum creatinine level. At a trough of 10 mg/liter, 89% of the study neonates had an AUC_0–24 of >400. Monte Carlo simulations demonstrated that troughs ranging from 7 to 11 mg/liter were highly predictive of an AUC_0–24 of >400 across a range of PMA, serum creatinine levels, and vancomycin doses. However, a trough of ≥10 mg/liter was not readily achieved in most simulated subgroups using routine starting doses. Higher starting doses frequently resulted in troughs of >20 mg/liter. A vancomycin trough of ∼10 mg/liter is likely adequate for most neonates with invasive MRSA infections based on considerations of the AUC_0–24. Due to pharmacokinetic and clinical heterogeneity in neonates, consistently achieving this target vancomycin exposure with routine starting doses is difficult. More robust clinical dosing support tools are needed to help clinicians with dose individualization.     

Compartmental Pharmacokinetics and Tissue Drug Distribution of the Pradimicin Derivative BMS 181184 in Rabbits

The pharmacokinetics of the antifungal pradimicin derivative BMS 181184 in plasma of normal, catheterized rabbits were characterized after single and multiple daily intravenous administrations of dosages of 10, 25, 50, or 150 mg/kg of body weight, and drug levels in tissues were assessed after multiple dosing. Concentrations of BMS 181184 were determined by a validated high-performance liquid chromatography method, and plasma data were modeled into a two-compartment open model. Across the investigated dosage range, BMS 181184 demonstrated nonlinear, dose-dependent kinetics with enhanced clearance, reciprocal shortening of elimination half-life, and an apparently expanding volume of distribution with increasing dosage. After single-dose administration, the mean peak plasma BMS 181184 concentration (C_max) ranged from 120 μg/ml at 10 mg/kg to 648 μg/ml at 150 mg/kg; the area under the concentration-time curve from 0 to 24 h (AUC_0–24) ranged from 726 to 2,130 μg · h/ml, the volume of distribution ranged from 0.397 to 0.799 liter/kg, and the terminal half-life ranged from 4.99 to 2.31 h, respectively (P < 0.005 to P < 0.001). No drug accumulation in plasma occurred after multiple daily dosing at 10, 25, or 50 mg/kg over 15 days, although mean elimination half-lives were slightly longer. Multiple daily dosing at 150 mg/kg was associated with enhanced total clearance and a significant decrease in AUC_0–24 below the values obtained at 50 mg/kg (P < 0.01) and after single-dose administration of the same dosage (P < 0.05). Assessment of tissue BMS 181184 concentrations after multiple dosing over 16 days revealed substantial uptake in the lungs, liver, and spleen and, most notably, dose-dependent accumulation of the drug within the kidneys. These findings are indicative of dose- and time-dependent elimination of BMS 181184 from plasma and renal accumulation of the compound after multiple dosing.     

Single- and Repeated-Dose Pharmacokinetics of Ceftaroline in Plasma and Soft Tissues of Healthy Volunteers for Two Different Dosing Regimens of Ceftaroline Fosamil

Ceftaroline fosamil (CPT-F) is currently approved for use for the treatment of complicated skin and soft tissue infections and community-acquired pneumonia at 600 mg twice daily (q12h), but other dosing regimens are under evaluation. To date, very limited data on the soft tissue pharmacokinetics (PK) of the active compound, ceftaroline (CPT), are available. CPT concentrations in the plasma, muscle, and subcutis of 12 male healthy volunteers were measured by microdialysis after single and repeated intravenous administration of 600 mg CPT-F q12h or three times daily (q8h) in two groups of 6 subjects each. Relevant PK and PK/pharmacodynamic (PD) parameters were calculated and compared between groups. In plasma, the area under the concentration-time curve (AUC) from 0 to 24 h for total CPT and the cumulative percentage of the dosing interval during which the free drug concentrations exceeded the MIC (fT_MIC) for unbound CPT for the currently established threshold of 1 mg/liter were significantly higher in the group receiving CPT-F q8h. Exposure to free drug in soft tissues was higher in the group receiving CPT-F q8h, but high interindividual variability in relevant PK parameters was observed. The mean ratios of the AUC from time zero to the end of the dosing interval (AUC_0-τ) for free CPT in soft tissues and the AUC_0-τ for the calculated free fraction in plasma at steady state ranged from 0.66 to 0.75. Administration of CPT-F q8h led to higher levels of drug exposure in all investigated compartments. When MIC values above 1 mg/liter were assumed, the calculated fT_MIC after dosing q12h was markedly lower than that after dosing q8h. The clinical implications of these differences are discussed in light of recently completed clinical phase III and PK/PD studies.     

Decreasing the time to achieve therapeutic vancomycin concentrations in critically ill patients: developing and testing of a dosing nomogram

Introduction

Achievement of optimal vancomycin exposure is crucial to improve the management of patients with life-threatening infections caused by susceptible Gram-positive bacteria and is of particular concern in patients with augmented renal clearance (ARC). The aim of this study was to develop a dosing nomogram for the administration of vancomycin by continuous infusion for the first 24 hours of therapy based on the measured urinary creatinine clearance (8 h CL_CR).

Methods

This single-center study included all critically ill patients treated with vancomycin over a 13-month period (group 1), in which we retrospectively assessed the correlation between vancomycin clearance and 8 h CL_CR. This data was used to develop a formula for optimised drug dosing. The efficiency of this formula was prospectively evaluated in a second cohort of 25 consecutive critically ill patients (group 2). Vancomycin serum concentrations between 20 to 30 mg/L were considered adequate. ARC was defined as 8 h CL_CR more than 130 ml/min/1.73 m².

Results

The incidence of ARC was 36% (n = 29/79) and 40% (10/25) in group 1 (n = 79) and 2 (n = 25), respectively. The mean serum vancomycin concentration on day 1 was 21.5 (6.4) and 24.5 (5.2) mg/L, for both groups respectively. On the treatment day, vancomycin plasma clearance was 5.12 (1.9) L/h in group 1 and correlated significantly with the 8 h CL_CR (r² = 0.66; P <0.001). The achievement of adequate vancomycin serum concentrations in group 2 was 84% (n = 21/25) versus 51% (n = 40/79) – P <0.005.

Conclusions

This new vancomycin nomogram enabled the achievement of adequate serum concentrations in 84% of the patients on the first day of treatment.     

Daptomycin Pharmacokinetics and Pharmacodynamics in a Pooled Sample of Patients Receiving Thrice-Weekly Hemodialysis

While the pharmacokinetic (PK) properties of daptomycin in hemodialysis (HD) patients have been evaluated previously by three groups, resultant dosing recommendations have varied. To address this clinical conundrum, this study combined concentration-time data from these PK evaluations and derived uniform dosing recommendations among patients on HD receiving daptomycin. A two-compartment model with separate HD and non-HD clearance terms was fit to the PK data from these studies by using BigNPAG. Embedded with PK parameters from the population PK analysis, 5,000-subject Monte Carlo simulations (MCS) were performed to identify HD dosing schemes that provided efficacy (cumulative and daily area under the concentration-time curve [AUC] values) and toxicity (trough concentrations of ≥24.3 mg/liter) profiles comparable to those from simulations employing the daptomycin PK model derived from the Staphylococcus aureus bacteremia–infective endocarditis (SAB-IE) study. Separate HD dosing schemes were sought for the two weekly interdialytic periods (48 and 72 h). For the 48-h interdialytic period, intra- and post-HD dosing provided the most isometric cumulative and daily AUCs. For the 72-h interdialytic period, all HD dosing schemes provided noncumulative AUC values from 48 to 72 h (AUC_48–72) that were <50% of the SAB-IE AUC_48–72 values. Increasing the parent dose by 50% intra- or post-HD provided comparable AUC_48–72 values, while maintaining acceptable trough concentration (C_min) values. When efficacy and toxicity profiles were evaluated for each individual study, higher probabilities for C_min reaching ≥24.3 mg/liter were observed in one of the three studies. Given the high probability of C_min being ≥24.3 mg/liter in one of the three studies, more intensive creatine phosphokinase (CPK) monitoring may be warranted in HD patients receiving daptomycin.     

Population Pharmacokinetic Study of Amikacin Administered Once or Twice Daily to Febrile, Severely Neutropenic Adults

Once-daily (o.d.) administration of 20 mg of amikacin per kg of body weight to neutropenic patients has been validated by clinical studies, but amikacin pharmacokinetics have been documented only for the 7.5-mg/kg twice-daily (b.i.d.) regimen in this population. In order to determine in neutropenic patients (i) the influence of the dosing regimen on the kinetics of amikacin, (ii) the linearity of kinetics of amikacin in the range of 7.5 to 20 mg/kg, and (iii) the influence of patient characteristics on the disposition of amikacin and (iv) to provide a rationale for dosing recommendations, we evaluated the population pharmacokinetics of amikacin administered to 57 febrile neutropenic adults (neutrophil count, <500/mm³) being treated for a hematological disorder and receiving amikacin at 7.5 mg/kg b.i.d. (n = 29) or 20 mg/kg o.d. (n = 28) and administered intravenously over 0.5 h. A total of 278 blood samples were obtained (1 to 14 samples per patient) during one or several administration intervals (1 to 47). Serum amikacin levels were measured by the enzyme-multiplied immunoassay technique. A mixed-effect modeling approach was used to fit a bicompartmental model to the data (NONMEM software). The influences of the dosing regimen and the demographic and biological indices on the pharmacokinetic parameters of amikacin were evaluated by the maximum-likelihood ratio test on the population model. The dosing regimen had no influence on amikacin pharmacokinetic parameters, i.e., the kinetics of amikacin were linear over the range of 7.5 to 20 mg/kg. Amikacin elimination clearance (CL) was only correlated with creatinine clearance or its covariates, namely, sex, age, body weight, and serum creatinine level. The interindividual variability of CL was 21%, while those of the central volume of distribution, the distribution clearance, and the tissue volume of distribution were 15, 30, and 25%, respectively. On the basis of the expected distribution of amikacin concentrations in this population, dosing recommendations as a function of creatinine clearance (CL_CR) are proposed: for patients with normal renal function (CL_CR of 80 to 130 ml/min), 20 mg/kg o.d. is recommended, whereas for patients with severe renal impairment (CL_CR, 10 to 20 ml/min), a dosage of 17 mg/kg every 48 h is recommended.     

Influence of Renal Failure on Ciprofloxacin Pharmacokinetics in Rats

Ciprofloxacin pharmacokinetics have been shown to be modified in patients with renal failure (e.g., the intestinal secretion of ciprofloxacin is increased). This study investigated the influence of renal failure on the pharmacokinetics of ciprofloxacin following oral and parenteral administration to rats of a dose of 50 mg/kg of body weight. After parenteral administration, only renal clearance (CL_R) was reduced in nephrectomized rats (5.3 ± 1.4 versus 17.8 ± 4.7 ml/min/kg, P < 0.01, nephrectomized versus control rats). However, nonrenal clearance was increased in nephrectomized rats (32 ± 4 versus 15 ± 5 ml/min/kg, P < 0.01, nephrectomized versus control rats), suggesting compensatory mechanisms for reduced renal function. After oral administration, apparent total clearance and CL_R were reduced (P < 0.01) in nephrectomized rats (117 ± 25 and 6.8 ± 4.4 ml/min/kg, respectively) compared with the values for control rats (185 ± 9 and 22.6 ± 5.3 ml/min/kg, respectively) and the area under the concentration-time curve was higher (P < 0.01) for nephrectomized rats (436.3 ± 90.5 mg · min/liter) than for control rats (271.3 ± 14.3 mg · min/liter). Terminal elimination half lives in the two groups remained constant after oral and parenteral administration. These results suggest an increased bioavailability of ciprofloxacin in nephrectomized rats, which was confirmed by a nonlinear mixed-effect model.     

Pharmacokinetics and Pharmacodynamics of Levornidazole in Patients With Intra-abdominal AnaerobicInfection

Purpose

The pharmacokinetic (PK) and pharmacodynamic characteristics of levornidazole were studied in patients with intra-abdominal anaerobic infection to provide the rationale of new clinical dosing regimen of levornidazole.

Pharmacodynamics of minocycline against Staphylococcus aureus in an in vitro pharmacokinetic model

Free drug serum concentrations of minocycline associated with the doses given to humans (100 mg every 12 hours for 24 hours) were simulated in an in vitro hollow-fiber pharmacokinetic model. Four strains of methicillin (meticillin)-resistant Staphylococcus aureus (MRSA), United Kingdom EMRSA 15 and 16 plus a pair of blood culture isolates before and after long-term minocycline treatment, were employed. The minocycline MICs for these four strains were 0.04 mg/liter, 0.19 mg/liter, 0.06 mg/liter, and 0.75 mg/liter. The antibacterial effect (ABE) of minocycline was measured using the area under the bacterial kill curve to 24 h (AUBKC) and the log change in viable count at 24 h (d24). The ABEs of minocycline with and without the addition of rifampin (rifampicin) were compared to those of vancomycin, and dose escalation and fractionation were used to determine the dominant pharmacodynamic index and its size. Minocycline alone produced a 1.5- to 2.0-log₁₀-unit reduction in viable count for the strains with MICs of <0.2 mg/liter, while the addition of rifampin increased the ABE for these strains (P < 0.05). Vancomycin simulations produced a reduction in viable counts of 2.8 to 4.5 log units at 24 h, which was equivalent to the minocycline-plus-rifampin combination. Free area under the concentration-time curve (AUC)/MIC was best related to AUBKC or d24 using a sigmoid maximal effect (Emax) model with r² of 0.92 and 0.87, respectively, and the AUC/MIC ratios for no change and −1-log-unit, −2-log-unit, and −3-log-unit drop at 24 h were 33.9, 75.9, 1,350, and >2,000, respectively. Fractionation of the dose at free AUC/MICs associated with human doses showed no difference between once, twice, or three times a day dosing. In contrast, fractionation of the dose at a free AUC associated with a static effect indicated that once daily dosing was superior. These data show that minocycline is an AUC/MIC-driven agent at human exposures and that the addition of rifampin may offer benefit in terms of MRSA killing.     

Moxifloxacin's Limited Efficacy in the Hollow-Fiber Model of Mycobacterium abscessus Disease

Current regimens used to treat pulmonary Mycobacterium abscessus disease have limited efficacy. There is an urgent need for new drugs and optimized combinations and doses. We performed hollow-fiber-system studies in which M. abscessus was exposed to moxifloxacin lung concentration-time profiles similar to human doses of between 0 and 800 mg/day. The minimum bactericidal concentration and MIC were 8 and 2 mg/liter, respectively, in our M. abscessus strain, suggesting bactericidal activity. Measurement of the moxifloxacin concentrations in each hollow-fiber system revealed an elimination rate constant (k_el) of 0.11 ± 0.05 h⁻¹ (mean ± standard deviation) (half-life of 9.8 h). Inhibitory sigmoid maximal effect (E_max) modeling revealed that the highest E_max was 3.15 ± 1.84 log₁₀ CFU/ml on day 3, and the exposure mediating 50% of E_max (EC₅₀) was a 0- to 24-h area under the concentration time curve (AUC_0–24)-to-MIC ratio of 41.99 ± 31.78 (r² = 0.99). The EC₈₀ was an AUC_0–24/MIC ratio of 102.11. However, no moxifloxacin concentration killed the bacteria to burdens below the starting inoculum. There was regrowth beyond day 3 in all doses, with replacement by a resistant subpopulation that had an MIC of >32 mg/liter by the end of the experiment. A quadratic function best described the relationship between the AUC_0–24/MIC ratio and the moxifloxacin-resistant subpopulation. Monte Carlo simulations of 10,000 patients revealed that the 400- to 800-mg/day doses would achieve or exceed the EC₈₀ in ≤12.5% of patients. The moxifloxacin susceptibility breakpoint was 0.25 mg/liter, which means that almost all M. abscessus clinical strains are moxifloxacin resistant by these criteria. While moxifloxacin''s efficacy against M. abscessus was poor, formal combination therapy studies with moxifloxacin are still recommended.