James R. Lane

Model Appropriateness and Population Pharmacokinetic Modeling

The purpose of this study was to define model appropriateness, identifying the individual elements thereof, and to set out a framework within which model appropriateness could be determined for population pharmacokinetic (PPK) models. Model appropriateness was defined by stating the problem to be solved, with the intended use of the model being the pivotal event. The elements of model appropriateness were identified with the type of model (descriptive vs. predictive) determining which elements of model appropriateness need to be executed. An example is presented to show how model appropriateness is determined for the optimal application of PPK models. It was determined that PPK models are developed to solve problems. Model appropriateness depends on identifying the problem, as well as stating the intended use of the model, and requires evaluation of the model for goodness of fit, reliability, and stability if intended for descriptive purposes; for predictive models, validation would be an additional requirement. Descriptive models are used to explain variability in the pharmacokinetics (PK) of a drug, while predictive models are developed to extrapolate beyond the immediate study population. For those models used for predictive purposes, strong assumptions are made about the relationship to the underlying population from which the data were collected. As an example of determining model appropriateness, a PPK model for 5‐fluorocytosine was developed, using NONMEM, version IV. The model was evaluated and validated by the process of percentile bootstrapping. From the PPK model, the range of expected serum concentrations based on two widely used dosing methods (Sanford and the University of California at San Diego [UCSD]) was simulated (Pharsight Trial Designer software). These results indicated that the UCSD method performed well and has the advantage of recommending convenient dosing intervals. In conclusion, considering and applying the principles of model appropriateness to PPK models will result in models that can be applied for their intended use with confidence. Model appropriateness was efficiently established and determined to address the problem of comparing competing dosing strategies.

Population Pharmacokinetics III: Design, Analysis, and Application of Population Pharmacokinetic Studies

OBJECTIVE To present a framework within which population pharmacokinetic (PPK) studies should be designed and analyzed and discuss the application of developed PPK models. METHODS Information on PPK was retrieved from a MEDLINE search (1979–December 2003) of the literature and a bibliographic evaluation of review articles and books. This information is used in conjunction with experience to explain the design and analysis of PPK studies. Also, examples are included to demonstrate the usefulness of PPK. SYNTHESIS A great deal of thought must be given to the design and analysis of PPK studies (ie, development of PPK models). Models are of 2 primary types—descriptive and predictive—and the process applied to these models is necessarily different. An approach that ensures model applicability is presented. CONCLUSIONS PPK models have great utility, and the applications are many. They are very different from single-subject pharmacokinetic models and therefore require different approaches to model estimation.

Increased incidence of cutaneous squamous cell carcinoma in lung transplant recipients taking long-term voriconazole

BACKGROUND Voriconazole has been used for prevention and treatment of fungal infections in patients after lung transplantation. We postulate that long-term use of voriconazole may increase the risk of squamous cell carcinoma of the skin in these patients. METHODS The study included 120 patients who received lung transplantation at UC San Diego Health System between July 2000 and June 2006. All patients received a similar initial immunosuppression regimen, and 43 (35.8%) received voriconazole for treatment or prophylaxis for fungal diseases. In this retrospective study, we compared the incidence of squamous cell carcinoma in lung transplant recipients with or without voriconazole use. RESULTS Squamous cell carcinomas developed in 39.5% of patients (17 of 43) who received voriconazole for prophylaxis or treatment of fungal disease, compared with 19.5% (15 of 77) who did not receive voriconazole (p = 0.03). Four patients died of metastatic squamous cell carcinoma, all in the voriconazole group. Multiple logistic regression analysis showed older age at the time of transplant (odds ratio [OR], OR (95% CI) 2.8 (1.5-5.5)), skin cancer pre-transplant (OR, 11.0 (1.76-68.4), and longer voriconazole therapy (OR, 1.8 (1.3-2.6)) were independent risk factors for development of skin cancer after transplant. CONCLUSIONS Our results suggest that long-term use of voriconazole may be associated with development of cutaneous squamous cell carcinoma in patients after lung transplant. Greater clinical aggressiveness of skin cancer was also noted in these patients.

Pharmacodynamic Characteristics of Nephrotoxicity Associated With Vancomycin Use in Children

BACKGROUND Limited studies incorporating population-based pharmacokinetic modeling have been conducted to determine pharmacodynamic indices associated with nephrotoxicity during vancomycin exposure in children. METHODS A retrospective cohort analysis was conducted from September 2003 to December 2011 at 2 hospitals. Nephrotoxicity was defined as an increase in serum creatinine concentration (SCr) by ≥0.5 mg/dL, or ≥50% increase in baseline SCr, either persisting for ≥2 consecutive days. A 1-compartment model with first-order kinetics was used in NONMEM 7.2 to estimate trough concentrations (Cmin) and area under the curve over 24 hours (AUC). Univariate, classification and regression tree (CART), and multivariate analyses were conducted to identify factors contributing to nephrotoxicity. RESULTS The analyses included 680 pediatric subjects with 1576 vancomycin serum concentrations. Based on univariate analysis, median Cmin (14.2 [interquartile range, IQR, 7.1-25.4] vs 8.4 [IQR, 5.5-12.4] mcg/mL; P = .001) and AUC (544 [IQR, 359-801] vs 378 [IQR, 304-494]; P < .001) were significantly higher in the nephrotoxic group compared with the non-nephrotoxic group. Using CART, we discovered that subjects with doses ≥60 mg/kg per day and AUC >1063 mg-h/L had a significantly higher occurrence of nephrotoxicity (P = .005). Adjusting for intensive care unit stay and concomitant nephrotoxic drugs, steady-state vancomycin Cmin ≥15 mcg/mL (adjusted odds ratio [aOR], 2.5; 95% confidence interval [CI], 1.1-5.8; P = .028) and AUC ≥800 mg-h/L (aOR, 3.7; 95% CI, 1.2-11.0; P = .018) were associated with increased risk of nephrotoxicity. CONCLUSIONS Our study describes the pediatric exposure-nephrotoxicity relationships for vancomycin. Vancomycin Cmin ≥15 mcg/mL and AUC ≥800 mg-h/L in children are independently associated with a > 2.5-fold increased risk of nephrotoxicity and may provide justification for use of alternative antibiotics in selected situations.

Inhibition of pentagastrin-stimulated gastric acid secretion by pantoprazole and omeprazole in healthy adults

Our objective was to compare the onset and duration of a single dose of pantoprazole or omeprazole on maximally stimulated gastric acid secretion. This double-blind, randomized, placebo-controlled study involved 36 healthy adults and utilized continuous pentagastrin infusion to stimulate acid secretion after administration of pantoprazole, 40 mg, omeprazole, 20 mg, or placebo. Gastric aspirates were collected over 24 hr and analyzed for volume, pH, and hydrogen ion concentration, and gastric acid outputs (GAO) were calculated. Comparison between GAO and intragastric pH was performed. Pantoprazole resulted in significantly greater inhibition of GAO than omeprazole. Mean cumulative 24-hr GAO was 164 ± 130 mEq for pantoprazole versus 283 ± 159 mEq for omeprazole (P = 0.031). Pantoprazole patients reached and maintained GAO levels below the 10-mEq/hr threshold at 5.7 hr, whereas omeprazole patients never reached this threshold. We conclude that pantoprazole significantly suppressed gastric acid secretion compared to omeprazole. Comparisons between pH and GAO showed that GAO was a more appropriate measure of gastric acid secretion than intragastric pH.

Pharmacokinetics of the Digoxin-Quinidine Interaction via Mixed-Effect Modelling

SummaryIt was the purpose of this study to evaluate the effect of quinidine administration on the population estimates of the volume of distribution (Vdpop) and clearance (CLpop) of digoxin. The data collected on 94 patients included 230 measured serum digoxin concentrations, height, age, sex, weight (wt), serum creatinine, history of digoxin and quinidine administration and the presence or absence of congestive heart failure (CHF). Using the NONMEM software program, estimates were obtained for CLpop and Vdpop. Variables tested for inclusion in the CLpop model were creatinine clearance (CLCR), CHF, wt, ideal bodyweight, quinidine (QUIN) [both as a discrete variable and in a dose-dependent manner], and body surface area. Variables tested for inclusion in the Vdpop model were CLCR, wt, ideal bodyweight, body surface area and quinidine. During model building a p-value of 0.05 was chosen for variable inclusion. The final model was as follows:

Direct Comparison of Three Methods For Predicting Digoxin Concentrations

\matrix{{{\rm{C}}{{\rm{L}}_{{\rm{pop}}}}({\rm{L}}/{\rm{h}}) = (3.1 + 0.0516 \times {\rm{C}}{{\rm{L}}_{{\rm{CR}}}}) \times {\rm{QUIN}}} \cr {{\rm{V}}{{\rm{d}}_{{\rm{pop}}}}({\rm{L}}) = (4.03 + 0.0832 \times {\rm{C}}{{\rm{L}}_{{\rm{CR}}}}) \times {\rm{wt}}} \cr {{\rm{F}} = 0.82} \cr}

Use of Pharmacokinetic and Pharmacodynamic Analyses to Determine the Optimal Fixed Dosing Regimen of Iclaprim for Treatment of Serious Gram-Positive Infections

where F is bioavailability. In the above, QUIN is 0.567 if quinidine is being concurrently administered and 1.0 if it is not. The coefficient of variation (CV) of CLpop was 44% while that of Vdpop was 48%. The residual intrasubject CV was 26%. These results compare favourably with previously derived methods of estimating digoxin CLpop and Vdpop but may improve on those methods due to the inclusion of quinidine in the model. These better estimates should result in improved initial dosage of digoxin.