A curated list of scientific journal articles on related software and contributions from the Rx Studio Team members.
Socio-Economic Validation of Precision Dosing Software
Peer-Reviewed Drug Models Available on Rx Studio Platform
BackgroundDespite being in clinical use for about 6 decades, vancomycin dosing remains perplexing and complex.
MethodsA population pharmacokinetic modeling and simulation approach was used to evaluate the efficiency of the current nomogram-based dosing of vancomycin. Serum vancomycin concentrations were obtained as a part of routine therapeutic drug monitoring from two 500-bed academic medical centers. A population pharmacokinetic model was first built using these therapeutic drug monitoring data. Population pharmacokinetic modeling was conducted using NONMEM (7.2 and 7.3). The forward addition-backward elimination approach was used to test the covariate effects. Appropriate numerical and visual criteria were used as model diagnostics for checking model appropriateness and model qualification. The current nomogram efficiency was evaluated by determining the percentage of subjects in the therapeutic range (10-20 mg/L).
ResultsA 2-compartment model with between-subject variability on clearance (CL), central volume of distribution (Vc), and peripheral volume of distribution best fit the data. Blood urea nitrogen, age, creatinine clearance, and hemodialysis status were significant covariates on clearance. Hemodialysis status was a significant covariate on Vc and peripheral volume of distribution. In the final model, creatinine clearance was retained as a covariate on CL whereas hemodialysis status was retained as covariate on both CL and Vc. Using Monte Carlo simulations, the current nomogram was optimized by the addition of a loading dose and reducing the maintenance doses. The current nomogram is suboptimal. Optimization of the nomogram resulted in >40% subjects consistently being in the therapeutic range at troughs collected after the first 6 doses.
ConclusionsCL and Vc differ markedly between patients undergoing hemodialysis and those not undergoing hemodialysis. Dosing nomogram based on these covariate relationships may potentially help in accurate dosing of vancomycin.
This study determines vancomycin (VAN) population pharmacokinetics (PK) in adult patients with hematological malignancies. VAN serum concentration data (n = 1,004) from therapeutic drug monitoring were collected retrospectively from 215 patients. A one-compartment PK model was selected. VAN pharmacokinetics population parameters were generated using the NONMEM program. A graphic approach and stepwise generalized additive modeling were used to elucidate the preliminary relationships between PK parameters and clinical covariates analyzed. Covariate selection revealed that total body weight (TBW) affected V, whereas renal function, estimated by creatinine clearance, and a diagnosis of acute myeloblastic leukemia (AML) influenced VAN clearance. We propose one general and two AML-specific models. The former was defined by CL (liters/h) = 1.08 × CLCR(Cockcroft and Gault) (liters/h); CVCL = 28.16% and V (liters) = 0.98 × TBW; CVV =37.15%. AML models confirmed this structure but with a higher clearance coefficient (1.17). The a priori performance of the models was evaluated in another 59 patients, and clinical suitability was confirmed. The models were fairly accurate, with more than 33% of the measured concentrations being within ±20% of the predicted value. This therapeutic precision is twofold higher than that of a noncustomized population model (16.1%). The corresponding standardized prediction errors included zero and a standard deviation close to unity. The models could be used to estimate appropriate VAN dosage guidelines, which are not clearly defined for this high-risk population. Their simple structure should allow easy implementation in clinical software and application in dosage individualization using the Bayesian approach.
After nearly 4 decades of clinical use, vancomycin (VAN) has maintained an important and uncontested niche in the antibacterial arsenal owing to its consistent activity against almost all gram-positive bacteria. However, the emergence and gradually increasing prevalence of vancomycin-resistant organisms in recent years have led to its administration being limited to specific indications.
The empirical use of VAN in persistently febrile neutropenic patients remains controversial. Currently, the prevalent opinion is for a restrictive use of glycopeptides, i.e., only for patients whose infection requires them, based on the microbiological data and a rigorous clinical evaluation of the patient. From a practical standpoint, this postulate implies, first, a rational antibiotic selection based on potential pathogens and, second, optimal use, including the drug dose and duration of therapy. In this sense, the population approach and pharmacodynamic criteria have become available as tools in individualized antimicrobial therapy, leading to increased efficacy and reduced selection of resistance. In order to apply such a strategy in everyday clinical practice, the precise pharmacokinetic (PK)-pharmacodynamic index determining efficacy and its target value as well as population PK parameters obtained from specific cohorts (oncology, intensive care unit, etc.) must be known or estimated.
A specific glycopeptide-treated population benefiting from this approach could be patients with hematological malignancies, owing to their high risk of developing life-threatening bacterial infections and the need for higher-than-expected dosages. However, little is known about the VAN pharmacokinetics in these patients since only one population PK analysis has been published. The methodological and sampling size constraints of this work suggested the need for studies aimed at improving our knowledge about the PK behavior of this drug in this particular group of patients. Other populations of patients with nonhematological diseases, mainly pediatric, treated with VAN have been appropriately characterized using the most usual and suitable population approach of mixed-effect modeling implemented in the NONMEM program.
On this basis, the information obtained should provide specific PK parameters to estimate appropriate dosage guidelines, which are not clearly defined for this high-risk population.
The first consensus guideline for therapeutic monitoring of vancomycin in adult patients was published in 2009. A committee representing 3 organizations (the American Society for Health-System Pharmacists [ASHP], Infectious Diseases Society of America [IDSA], and Society for Infectious Diseases Pharmacists [SIDP]) searched and reviewed all relevant peer-reviewed data on vancomycin as it related to in vitro and in vivo pharmacokinetic and pharmacodynamic (PK/PD) characteristics, including information on clinical efficacy, toxicity, and vancomycin resistance in relation to serum drug concentration and monitoring. The data were summarized, and specific dosing and monitoring recommendations were made. The primary recommendations consisted of eliminating routine monitoring of serum peak concentrations, emphasizing a ratio of area under the curve over 24 hours to minimum inhibitory concentration (AUC/MIC) of ≥400 as the primary PK/PD predictor of vancomycin activity, and promoting serum trough concentrations of 15 to 20 mg/L as a surrogate marker for the optimal vancomycin AUC/MIC if the MIC was ≤1 mg/L in patients with normal renal function. The guideline also recommended, albeit with limited data support, that actual body weight be used to determine the vancomycin dosage and loading doses for severe infections in patients who were seriously ill.
Since those recommendations were generated, a number of publications have evaluated the impact of the 2009 guidelines on clinical efficacy and toxicity in patients receiving vancomycin for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections. It should be noted, however, that when the recommendations were originally published, there were important issues not addressed and gaps in knowledge that could not be covered adequately because of insufficient data. In fact, adequate data were not available to make recommendations in the original guideline for specific dosing and monitoring for pediatric patients outside of the neonatal age group; specific recommendations for vancomycin dosage adjustment and monitoring in the morbidly obese patient population and patients with renal failure, including specific dialysis dosage adjustments; recommendations for the use of prolonged or continuous infusion (CI) vancomycin therapy; and safety data on the use of dosages that exceed 3 g per day. In addition, there were minimal to no data on the safety and efficacy of targeted trough concentrations of 15 to 20 mg/L.
This consensus revision evaluates the current scientific data and controversies associated with vancomycin dosing and serum concentration monitoring for serious MRSA infections (including but not limited to bacteremia, sepsis, infective endocarditis, pneumonia, osteomyelitis, and meningitis) and provides new recommendations based on recent available evidence. Due to a lack of data to guide appropriate targets, the development of this guideline excluded evaluation of vancomycin for methicillin-susceptible S. aureus (MSSA) strains, coagulase-negative staphylococci, and other pathogens; thus, the extrapolation of guideline recommendations to these pathogens should be viewed with extreme caution. Furthermore, serious invasive MRSA infections exclude nonbacteremic skin and skin structure and urinary tract infections. Since this guideline focuses on optimization of vancomycin dosing and monitoring, recommendations on the appropriateness of vancomycin use, combination or alternative antibiotic therapy, and multiple medical interventions that may be necessary for successful treatment of invasive MRSA infections are beyond the scope of this guideline and will not be presented.
ObjectiveTo evaluate the predictive performance of eight renal function equations to describe amikacin elimination in a large standard population with a wide range of age.
MethodsRetrospective study of adult hospitalized patients treated with amikacin and monitored in the clinical pharmacokinetics laboratory of a pharmacy service. Renal function was calculated as Cockcroft-Gault with total, adjusted and ideal body weight, MDRD-4, CKD-EPI, rLM, BIS1, and FAS. One compartment model with first-order elimination, including interindividual variability on clearance and volume of distribution and combined residual error model was selected as a base structural model. A pharmaco-statistical analysis was performed following a non-linear mixed effects modeling approach (NONMEM 7.3 software).
Results198 patients (61 years [18–93]) and 566 measured amikacin plasma concentrations were included. All the estimated glomerular filtration rate and creatinine clearance equations evaluated described properly the data. The linear relationship between clearance and glomerular filtration rate based on rLM showed a statistically significant improvement in the fit of the data. rLM must be evaluated carefully in renal failure for amikacin dose adjustment.
ConclusionsRevised Lund-Malmö (rLM) and CKD-EPI showed the superior predictive performance of amikacin drug elimination comparing to all the alternative metrics evaluated.
PurposeTo develop a meropenem population pharmacokinetic model in critically ill patients with particular focus on optimizing dosing regimens based on renal function.
MethodsPopulation pharmacokinetic analysis was performed with creatinine clearance (CrCl) and adjusted body weight to predict parameter estimates. Initial modeling was performed on 21 patients (55 samples). Validation was conducted with 12 samples from 5 randomly selected patients excluded from the original model. A 5,000-patient Monte Carlo simulation was used to ascertain optimal dosing regimens for three CrCl ranges.
ResultsMean ± SD age, APACHE, and CrCl were 59.2 ± 16.8 years, 13.6 ± 7, and 78.3 ± 33.7 mL/min. Meropenem doses ranged from 0.5 g every 8 h (q8h)-2 g q8h as 0.5-3 h infusions. Median estimates for volume of the central compartment, K₁₂ and K₂₁ were 0.24 L/kg, 0.49 h⁻¹, and 0.65 h⁻¹, respectively. K₁₀ was described by the equation: K₁₀= 0.3922 + 0.0025 × CrCl. Model bias and precision were -1.9 and 8.1 mg/L. R², bias, and precision for the validation were 93%, 1.1, and 2.6 mg/L. At minimum inhibitory concentrations (MICs) up to 8 mg/L, the probability of achieving 40% fT > MIC was 96, 90, and 61% for 3 h infusions of 2 g q8h, 1 g q8h, and 1 g q12h in patients with CrCl ≥50, 30-49, and 10-29, respectively. Target attainment was 75, 65, and 44% for these same dosing regimens as 0.5 h infusions.
ConclusionsThis pharmacokinetic model is capable of accurately estimating meropenem concentrations in critically ill patients over a range of CrCl values. Compared with 0.5 h infusions, regimens employing prolonged infusions improved target attainment across all CrCl ranges.
ObjectivesTo develop a population pharmacokinetic model of meropenem in burn patients and to explore the appropriateness of current dosage regimens.
Patients and methodsFifty-nine patients with burns ranging from 3% to 97% of total body surface area treated with meropenem were analysed. The population pharmacokinetic parameters of meropenem in 59 burn patients were estimated, and concentrations were simulated by using a mixed effect method (NONMEM, ver. 6.2).
ResultsThe final model was a two-compartment model with first-order elimination where creatinine clearance (CLCR) and oedema contributed. The mean population pharmacokinetic parameters were clearance (L/h) = 4.45 + 10.5 × CLCR (mL/min)/138, V1 (central volume) = 17.0 + 11.1 × presence of oedema (0 or 1) L, V2 (peripheral volume) = 10.1 L and Q (intercompartmental clearance) = 5.25 L/h with interindividual variability (CV%) of 31.5%, 44.4%, 67.2% and 0% (not estimated), respectively.
ConclusionsThe population clearance and volume of distribution in our burn patients were significantly greater than those reported in non-burn patients. The simulation of 1000 virtual patients’ plasma meropenem concentration treated with 1000 mg (30 min infusion) every 8 h based upon the model predicted the probability of achieving the time above MIC > 40% of the dosing interval as 58.9% for Pseudomonas aeruginosa isolated from three university hospitals in Korea.
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 (CLCR) on overall clearance, TZP clearance was made proportional to the estimated CLCR. 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 CLCR. The traditional TZP regimen displayed the greatest variability in PTA across MIC values, especially for MIC values exceeding 4 mg/liter, when stratified by CLCR. In contrast, the PTA for the extended-infusion TZP regimen exceeded ≥80% for MIC values of ≤8 mg/liter across all CLCR strata. All regimens were associated with suboptimal PTA for MIC values of ≥32 mg/liter irrespective of the CLCR. The CLCR adjustments for traditional and extended-infusion TZP dosing regimens should be considered at a CLCR 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. 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). Among the studies that have characterized the ability of various TZP dosing strategies to achieve 50% fT > MIC, 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 (CLCR) 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.
BackgroundData suggest that higher doses of vancomycin can increase the risk of nephrotoxicity. No study has been undertaken to determine the pharmacodynamic index (ie, the area under the curve [AUC] or the trough value) that best describes the relationship between vancomycin exposure and onset of nephrotoxicity.
MethodsA retrospective study was conducted among patients who received vancomycin for a suspected or proven gram-positive infection during the period from 1 January 2005 through 31 December 2006 at Albany Medical Center Hospital. Patients were included in our study if they (1) were ⩾18 years old, (2) had an absolute neutrophil count of ⩾1000 cells/mm3, (3) received vancomycin for >48 h, (4) had ⩾1 vancomycin trough level collected within 96 h of vancomycin therapy, and (5) had a baseline serum creatinine level of <2.0 mg/dL. Patients were excluded if they (1) had a diagnosis of cystic fibrosis, (2) received intravenous contrast dye within 7 days of starting vancomycin or during therapy, or (3) required vasopressor support during therapy. Demographics, comorbid conditions, and treatment data were collected. The highest observed vancomycin trough value within 96 h of initiation of vancomycin therapy and the estimated vancomycin AUC were analyzed as measures of vancomycin exposure. The vancomycin AUC value from 0 to 24 h at steady state (in units of mg × h/L) for each patient was estimated by use of the maximum a posteriori probability Bayesian procedure in ADAPT II. Nephrotoxicity was defined as an increase in serum creatinine level of 0.5 mg/dL or 50%, whichever was greater, following initiation of vancomycin therapy. Logistic and Cox proportional hazards regression models identified the vancomycin pharmacodynamic index that best describes the relationship between vancomycin exposure and toxicity.
ResultsDuring the study period, 166 patients met the inclusion criteria. Both initial vancomycin trough values and 0–24-h at steady state AUC values were associated with nephrotoxicity in the bivariate analyses. However, the vancomycin trough value, modeled as a continuous variable, was the only vancomycin exposure variable associated with nephrotoxicity in the multivariate analyses.
ConclusionsThe results indicate that a vancomycin exposure-toxicity response relationship exists. The vancomycin trough value is the pharmacodynamic index that best describes this association.
Relevant Rx Studio Team Publications
Peer-reviewed scientific journal articles by our team members:
ObjectiveTo adapt an antibiotic dose adjustment software initially developed in English, to Portuguese and to the Brazilian context.
MethodsThis was an observational, descriptive study in which the Delphi method was used to establish consensus among specialists from different health areas, with questions addressing the visual and operational aspects of the software. In a second stage, a pilot experimental study was performed with the random comparison of patients for evaluation and adaptation of the software in the real environment of an intensive care unit, where it was compared between patients who used the standardized dose of piperacillin/tazobactam, and those who used an individualized dose adjusted through the software Individually Designed and Optimized Dosing Strategies.
ResultsTwelve professionals participated in the first round, whose suggestions were forwarded to the software developer for adjustments, and subsequently submitted to the second round. Eight specialists participated in the second round. Indexes of 80% and 90% of concordance were obtained between the judges, characterizing uniformity in the suggestions. Thus, there was modification in the layout of the software for linguistic and cultural adequacy, minimizing errors of understanding and contradictions. In the second stage, 21 patients were included, and there were no differences between doses of piperacillin in the standard dose and adjusted dose Groups.
ConclusionThe adapted version of the software is safe and reliable for its use in Brazil.
ObjectiveTo investigate whether hydrocortisone supplementation increases blood pressure and decreases inotrope requirements compared with placebo in cooled, asphyxiated neonates with volume-resistant hypotension.
Study DesignA double-blind, randomized, placebo-controlled clinical trial was conducted in a Level III neonatal intensive care unit in 2016-2017. Thirty-five asphyxiated neonates with volume-resistant hypotension (defined as a mean arterial pressure [MAP] < gestational age in weeks) were randomly assigned to receive 0.5 mg/kg/6 hours of hydrocortisone or placebo in addition to standard dopamine treatment during hypothermia.
ResultsMore patients reached the target of at least 5-mm Hg increment of MAP in 2 hours after randomization in the hydrocortisone group, compared with the placebo group (94% vs 58%, P = .02, intention-to-treat analysis). The duration of cardiovascular support (P = .001) as well as cumulative (P < .001) and peak inotrope dosage (P < .001) were lower in the hydrocortisone group. In a per-protocol analysis, regression modeling predicted that a 4-mm Hg increase in MAP in response to hydrocortisone treatment was comparable with the effect of 15 μg/kg/min of dopamine in this patient population. Serum cortisol concentrations were low before randomization in both the hydrocortisone and placebo groups (median 3.5 and 3.3 μg/dL, P = .87; respectively), suggesting inappropriate adrenal function. Short-term clinical outcomes were similar in the 2 groups.
ConclusionHydrocortisone administration was effective in raising the blood pressure and decreasing inotrope requirement in asphyxiated neonates with volume-resistant hypotension during hypothermia treatment.
Posters presented at conferences contributed by our team members: