Why has model-informed precision dosing not yet become common clinical reality? lessons from the past and a roadmap for the future.

Patient groups prone to polypharmacy and special subpopulations are susceptible to suboptimal treatment. Refined dosing in special populations is imperative to improve therapeutic response and/or lowering the risk of toxicity. Model-informed precision dosing (MIPD) may improve treatment outcomes by achieving the optimal dose for an individual patient. There is, however, relatively little published evidence of large-scale utility and impact of MIPD, where it is often implemented as local collaborative efforts between academia and healthcare. This article highlights some successful applications of bringing MIPD to clinical care and proposes strategies for wider integration in healthcare. Considerations are brought up herein that will need addressing to see MIPD become "widespread clinical practice," among those, wider interdisciplinary collaborations and the necessity for further evidence-based efficacy and cost-benefit analysis of MIPD in healthcare. The implications of MIPD on regulatory policies and pharmaceutical development are also discussed as part of the roadmap.

ABCC3 genetic variants are associated with postoperative morphine-induced respiratory depression and morphine pharmacokinetics in children.

Respiratory depression (RD) is a serious side effect of morphine and detrimental to effective analgesia. We reported that variants of the ATP binding cassette gene ABCC3 (facilitates hepatic morphine metabolite efflux) affect morphine metabolite clearance. In this study of 316 children undergoing tonsillectomy, we found significant association between ABCC3 variants and RD leading to prolonged postoperative care unit stay (prolonged RD). Allele A at rs4148412 and allele G at rs729923 caused a 2.36 (95% CI=1.28-4.37, P=0.0061) and 3.7 (95% CI 1.47-9.09, P=0.0050) times increase in odds of prolonged RD, respectively. These clinical associations were supported by increased formation clearance of morphine glucuronides in children with rs4148412 AA and rs4973665 CC genotypes in this cohort, as well as an independent spine surgical cohort of 67 adolescents. This is the first study to report association of ABCC3 variants with opioid-related RD, and morphine metabolite formation (in two independent surgical cohorts).

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for CYP3A5 Genotype and Tacrolimus Dosing.

Tacrolimus is the mainstay immunosuppressant drug used after solid organ and hematopoietic stem cell transplantation. Individuals who express CYP3A5 (extensive and intermediate metabolizers) generally have decreased dose-adjusted trough concentrations of tacrolimus as compared with those who are CYP3A5 nonexpressers (poor metabolizers), possibly delaying achievement of target blood concentrations. We summarize evidence from the published literature supporting this association and provide dosing recommendations for tacrolimus based on CYP3A5 genotype when known (updates at www.pharmgkb.org).

Review article: applying pharmacokinetics to optimise dosing of anti-TNF biologics in acute severe ulcerative colitis.

BACKGROUND: Acute severe ulcerative colitis (ASUC), the most aggressive presentation of ulcerative colitis (UC), occurs in 15% of adults and children with UC. First line therapy with intravenous corticosteroids is ineffective in half of adults and one-third of children. Therapeutic monoclonal antibodies against TNF (anti-TNF therapy) are emerging as a common treatment for ASUC due to their similar efficacy to calcineurin inhibitors and more favourable adverse effect profile. AIM: To comprehensively review the evidence for anti-TNF therapy for ASUC in children and adults with regard to outcomes and pharmacokinetics. METHODS: PubMed and recent conference proceedings were searched using the terms 'ulcerative colitis', 'acute severe ulcerative colitis', 'anti-TNF', 'pharmacokinetics' and the generic names of specific anti-TNF agents. RESULTS: Outcomes after anti-TNF therapy for ASUC remain suboptimal with about one half of children and adults undergoing colectomy. While several randomised controlled trials have demonstrated the efficacy of anti-TNF therapy for ambulatory patients with moderate to severely active UC, patients in these studies were less ill than those with ASUC. Patients with ASUC may exhibit more rapid clearance of anti-TNF biologics due to pharmacokinetic mechanisms influenced by disease severity. CONCLUSIONS: Conventional weight-based dosing effective in patients with moderately to severely active UC, may not be equally effective in those with acute severe ulcerative colitis. Personalised anti-TNF dosing strategies, which integrate patient factors and early measures of pharmacokinetics and response, hold promise for ensuring sustained drug exposure and maximising early mucosal healing in patients with acute severe ulcerative colitis.

Development of a Physiologically-Based Pharmacokinetic Model for Sirolimus: Predicting Bioavailability Based on Intestinal CYP3A Content.

Sirolimus is an inhibitor of mammalian target of rapamycin (mTOR) and is increasingly being used in transplantation and cancer therapies. Sirolimus has low oral bioavailability and exhibits large pharmacokinetic variability. The underlying mechanisms for this variability have not been explored to a large extent. Sirolimus metabolism was characterized by in vitro intrinsic clearance estimation. Pathway contribution ranked from CYP3A4 > CYP3A5 > CYP2C8. With the well stirred and Qgut models sirolimus bioavailability was predicted at 15%. Interindividual differences in bioavailability could be attributed to variable intestinal CYP3A expression. The physiologically-based pharmacokinetics (PBPK) model developed in Simcyp predicted a high distribution of sirolimus into adipose tissue and another elimination pathway in addition to CYP-mediated metabolism. PBPK model predictive performance was acceptable with Cmax and area under the curve (AUC) estimates within 20% of observed data in a dose escalation study. The model also showed potential to assess the impact of hepatic impairment and drug-drug interaction (DDI) on sirolimus pharmacokinetics.CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e59; doi:10.1038/psp.2013.33; published online 24 July 2013.

Clinical trial simulations in pediatric patients using realistic covariates: application to teduglutide, a glucagon-like peptide-2 analog in neonates and infants with short-bowel syndrome.

Teduglutide, a synthetic glucagon-like peptide-2 (GLP-2) analog with activity relating to the regeneration, maintenance, and repair of the intestinal epithelium, is currently being evaluated for the treatment of short-bowel syndrome (SBS), Crohn's disease, and other gastrointestinal disorders. On the basis of promising results from teduglutide studies in adults with SBS and from studies in neonatal and juvenile animal models, a pediatric multiple-dose phase I clinical study was designed to determine the safety, efficacy, and pharmacokinetics of teduglutide in pediatric patients with SBS who have undergone resection for necrotizing enterocolitis, malrotation, or intestinal atresia. This report details the application of clinical trial simulations coupled with a novel approach using generalized additive modeling for location, scale, and shape (GAMLSS) that facilitates the simulation of demographic covariates specific to the targeted patient populations. The goal was to optimize phase I dosing strategies and the likelihood of achieving target exposure and therapeutic effect.

Development of an optimal sampling strategy for clinical pharmacokinetic studies of the novel anthracycline disaccharide analogue MEN-10755.

AIM: MEN-10755 is a novel anthracycline analogue that has shown an improved therapeutic efficacy over doxorubicin in animal models, especially in gynaecological and lung cancers and is currently under clinical development for the treatment of solid tumours. The aim of the project was to develop an optimal sampling strategy for MEN-10755 to provide an efficient basis for future pharmacokinetic/pharmacodynamic investigations. METHODS: Data from 24 patients who participated in a phase I clinical pharmacokinetic study of MEN-10755 administered as a short i.v. infusion were included. Individual pharmacokinetic values were calculated by fitting the plasma concentration data to a two-compartment model using nonlinear least-squared regression (KINFIT, Ed 3.5). Population pharmacokinetic analysis was carried out using (a) the traditional standard two-stage method (STS) based on all data (KINFIT-ALL), (b) the iterative two-stage Bayesian (IT(2)B) population modelling algorithm (KINPOP), and (c) the STS method using KINFIT and using four optimally timed plasma concentrations (KINFIT-OSS4). Determinant (D) optimal sampling strategy (OSS) was used to evaluate the four most information-rich sampling times. The pharmacokinetic parameters V(c) (l), k(el) (h(-1)), k(12) (h(-1)) and k(21) (h(-1)) calculated using KINPOP served as a model for calculation of four D-optimal sampling times. D-optimal sampling data sets were analysed using KINFIT-OSS4 and compared with the population model obtained by the traditional standard two-stage approach for all data sets (KINFIT-ALL). RESULTS: The optimal sampling times were: the end of the infusion, and 1.5 h, 3.8 h and 24 h after the start of the infusion. The four-point D-optimal sampling design determined in this study gave individual parameter estimates close to the basic standard estimates using the full data set. CONCLUSION: Because accurate estimates of pharmacokinetic parameters were achieved, the four-point D-optimal sampling design may be very useful in future studies with MEN-10755.

Dry powder inhalation of antibiotics in cystic fibrosis therapy: part 2. Inhalation of a novel colistin dry powder formulation: a feasibility study in healthy volunteers and patients.

The aim of the present study was to perform a proof of principle study with a new colistin dry powder inhalation system in six healthy volunteers and five patients with cystic fibrosis. All subjects were asked to inhale 25 mg colistin sulfate dry powder. The patients were also asked to nebulize 160 mg colistin sulfomethate as a solution. Colistin serum concentrations were determined as an indirect parameter to compare both forms of administration. Pulmonary function tests were performed. Peak serum colistin concentrations ranged from 14 to 59 microg/l in volunteers after inhalation of 25 mg as dry powder. In patients, peak concentrations ranged from 18 to 64 microg/l after nebulization of 160 mg colistin sulfomethate solution and from 77 to 159 microg/l after inhalation of 25 mg colistin sulfate dry powder. Pulmonary function tests were not significantly different after inhalation of the dry powder by the volunteers nor after nebulization of the solution by the patients. In some patients a decrease in pulmonary function and moderate to severe cough was observed after inhalation of the dry powder. The new colistin inhaler provides an attractive alternative for nebulized colistin and was highly appreciated by the patients. The decrease in pulmonary function and cough in patients is a drawback, which may be overcome by dose reduction and a further improvement of the new dosage form.

High-performance liquid chromatographic method for the determination of colistin in serum.

Inhalation therapy of colistin is widespread in patients with cystic fibrosis. To date, no pharmacokinetic data of colistin after inhalation are available. To optimize the inhalation therapy, pharmacokinetic data of colistin are necessary. In this study, the authors describe a chromatographic analysis for measurement of colistin concentrations in serum. After protein precipitation, the colistin sample is treated with orthophthalaldehyde for derivatization. The sum of the peak areas of the two main components of colistin (polymyxin E1 and E2) were used for quantitation. The performance of the analytical method was assessed by determining the lower limit of quantitation, the selectivity of the method, the intra-assay variation, the reproducibility, the interassay variation, and the accuracy. The lower limit of quantitation was 28 microg/L. Ceftazidime, aztreonam, piperacilline, or tobramycin showed no interference with the colistin assay. In a pilot study, the authors found a trough value of approximately 10 microg/L and peak values of approximately 100 microg/L after inhalation of 160 mg colistin in serum samples of a representative patient. These values show that the method can be used to design further experiments. The applicability of the method was also tested on urine and sputum samples. Colistin was detectable but further validation experiments are required to confirm the usefulness of the method in these biologic matrices. To the authors' knowledge this is the first study in which serum concentrations are described after inhalation of colistin in patients with cystic fibrosis.

Pharmacokinetics of tobramycin in adults with cystic fibrosis: implications for once-daily administration.

Once-daily administration of aminoglycosides is routinely used in many institutions. However, comparative efficacy data for patients with cystic fibrosis (CF) are lacking. The purpose of the present study was to compare the predicted pharmacodynamic activity of tobramycin at 10 mg/kg of body weight/day administered every 24 h (q24h), q12h, and q8h. Pharmacokinetic (PK) data were derived from analysis of data on the drug concentration in sera from 60 adult CF patients. Individual maximum a posteriori probability Bayesian PK parameter values were used to construct serum concentration-versus-time curves and to determine various indices (peak concentration/MIC ratio [peak/MIC], area under the concentration-time curve/MIC ratio [AUC/MIC], and time that the concentration was less than the MIC [T

Pharmacokinetic optimisation of antibacterial treatment in patients with cystic fibrosis. Current practice and suggestions for future directions.

Antibacterials play a central role in the medical management of patients with cystic fibrosis (CF). Administration of adequate dosages of antibacterials results in pronounced beneficial effects on the morbidity and mortality of this patient group. The dosage of the antibacterial that is needed for optimal treatment depends on the individual patient's pharmacokinetics and the pharmacokinetic-pharmacodynamic effect on the micro-organism of relevance in the host. In general, the disposition of antibacterial drugs in patients with CF is not as 'atypical' as once thought. Recent research with adequately matched controls demonstrated that, for a few beta-lactam antibacterials only, a CF-specific increase of the total body clearance seems to exist and that the large volumes of distribution observed are the result of malnutrition and the relative lack of adipose tissue. Pharmacokinetic-pharmacodynamic relationships in patients with CF are less well studied. Apart from the pharmacokinetics, there is a need for optimisation of antibacterial therapy. For the aminoglycosides, pharmacokinetic optimisation based on measured serum drug concentrations is common practice. The Sawchuk-Zaske method based on peak and trough drug concentrations is widely used. A more sophisticated approach is the 'goal-oriented model-based Bayesian adaptive control' method, where integration of mathematically determined optimally (D-optimally) sampled serum drug concentrations and a population model results in the most likely set of individual pharmacokinetic parameter values suitable for further pharmacokinetic optimisation of the therapy. A future development is the integration of changing serum drug concentrations and killing rates of the target micro-organism to a pharmacokinetic-pharmacodynamic surrogate relationship to optimise drug therapy. The latter approach may be extremely useful in deciding on the frequency of aminoglycoside administration as well as the optimal use of the beta-lactam antibacterials and fluoroquinolones.

Continuous infusion of ceftazidime in cystic fibrosis patients during home treatment: clinical outcome, microbiology and pharmacokinetics.

Acute exacerbations of Pseudomonas aeruginosa lung infections were treated with ceftazidime by continuous infusion in 17 adult patients with cystic fibrosis at home. Ceftazidime was delivered via an infusion pump and the effects of this 3 week home intravenous antibiotic treatment (HIVAT) were prospectively studied over a 2 year period. Patients with cystic fibrosis (eight male and nine female patients; mean age 26.9 +/- 7.6 years, range 15-52 years), received a total of 33 courses of continuous ceftazidime (100 mg/kg/24 h). Clinical data were collected at the start, the end and 4-6 weeks after the end of treatment in 12 patients. Ceftazidime pharmacokinetic data during continuous infusion were obtained from ten patients. The treatment was supervised by the clinician without home visits. All 25 clinically evaluable courses in 12 patients proved efficacious. The mean duration of the courses was 21 days. The entire antibiotic course was administered at home in 88% of the courses. The other 12% was started for 2-3 days as an inpatient. Objective clinical parameters significantly improved. Clinical improvement was noted in 91% of the patients, and lasted at least until 4-6 weeks after the end of the treatment in 70%. The number of cultures positive for P. aeruginosa decreased significantly during antibiotic treatment. Bacterial count returned to pretreatment values 4-6 weeks after treatment. Multiple courses of ceftazidime monotherapy did not result in a lasting increase of ceftazidime-resistant pseudomonas strains. Total body clearance was 9.1 +/- 1.3 L/h. The steady-state ceftazidime serum concentration during continuous infusion was 28.4 +/- 5.0 mg/L. Sputum concentrations were in the range of 0.5-13 mg/L (3.9 +/- 4.0 mg/L). In conclusion, HIVAT with ceftazidime administered by continuous infusion proved clinically effective and did not result in an increase in lasting resistance.

Pharmacokinetic modelling of intravenous tobramycin in adolescent and adult patients with cystic fibrosis using the nonparametric expectation maximization (NPEM) algorithm.

The availability of personal computer programs for individualizing drug dosage regimens has stimulated the interest in modelling population pharmacokinetics. Data from 82 adolescent and adult patients with cystic fibrosis (CF) who were treated with intravenous tobramycin because of an exacerbation of their pulmonary infection were analysed with a non-parametric expectation maximization (NPEM) algorithm. This algorithm estimates the entire discrete joint probability density of the pharmacokinetic parameters. It also provides traditional parametric statistics such as the means, standard deviation, median, covariances and correlations among the various parameters. It also provides graphic-2- and 3-dimensional representations of the marginal densities of the parameters investigated. Several models for intravenous tobramycin in adolescent and adult patients with CF were compared. Covariates were total body weight (for the volume of distribution) and creatinine clearance (for the total body clearance and elimination rate). Because of lack of data on patients with poor renal function, restricted models with non-renal clearance and the non-renal elimination rate constant fixed at literature values of 0.15 L/h and 0.01 h-1 were also included. In this population, intravenous tobramycin could be best described by median (+/-dispersion factor) volume of distribution per unit of total body weight of 0.28 +/- 0.05 L/kg, elimination rate constant of 0.25 +/- 0.10 h-1 and elimination rate constant per unit of creatinine clearance of 0.0008 +/- 0.0009 h-1/(ml/min/1.73 m2). Analysis of populations of increasing size showed that using a restricted model with a non-renal elimination rate constant fixed at 0.01 h-1, a model based on a population of only 10 to 20 patients, contained parameter values similar to those of the entire population and, using the full model, a larger population (at least 40 patients) was needed.

Creatinine clearance as predictor of tobramycin elimination in adult patients with cystic fibrosis.

Assessment of renal function and relating this parameter to amino-glycoside clearance is important for an appropriate individualization of dosage regimens in patients with impaired renal function. However, it has been suggested that in cystic fibrosis (CF), creatinine clearance (CrCl) is not a good predictor of tobramycin clearance because of a lack of correlation. The aim of this study was to investigate the correlation between the tobramycin clearance and the measured CrCl. In addition, because most pharmacokinetic computer models use an a priori relationship between CrCl and tobramycin elimination rate constant [k(el)], regression analysis of k(el) on CrCl was performed. Eighteen CF patients (12 men, 6 women, ages 21-55 years) were treated with intravenous tobramycin. Blood and urine samples were collected for tobramycin analysis and determination of the CrCl. For each patient, CrCl was also estimated using the formulas of Cockcroft and Gault (C/G), Jelliffe I (J I), and Jelliffe II (J II). Predictive performance of these formulas was evaluated using mean error and mean squared error as reflections of bias and precision. Tobramycin total body clearance as well as renal clearance correlated significantly with CrCl (r = 0.52; p = 0.02 and r = 0.78; p = 0.02, respectively). Regression of the tobramycin k(el) versus CrCl gave the following equation: k(el) = 0.135 + 0.00134*CrCl/1.73 m2 (r = 0.64; p = 0.004). The 95% confidence interval of intercept and slope of the regression line were 0.019-0.251 and 0.00049-0.00219, respectively. The formulas of C/G, J I, and J II all overpredicted CrCl. Bias was 19, 24, and 8 ml/min, and precision was 37, 42, and 33 ml/min, respectively, for the C/G, J I, and J II formulas. In our CF population the J II formula gave the best estimation of the CrCl but calculated estimates deviated -25(-)+62% from measured values.

Population pharmacokinetics of ceftazidime in cystic fibrosis patients analyzed by using a nonparametric algorithm and optimal sampling strategy.

Postinfusion data obtained from 17 patients with cystic fibrosis participating in two clinical trials were used to develop population models for ceftazidime pharmacokinetics during continuous infusion. Determinant (D)-optimal sampling strategy (OSS) was used to evaluate the benefits of merging four maximally informative sampling times with population modeling. Full and sparse D-optimal sampling data sets were analyzed with the nonparametric expectation maximization (NPEM) algorithm and compared with the model obtained by the traditional standard two-stage approach. Individual pharmacokinetic parameter estimates were calculated by weighted nonlinear least-squares regression and by maximum a posteriori probability Bayesian estimator. Individual parameter estimates obtained with four D-optimally timed serum samples (OSS4) showed excellent correlation with parameter estimates obtained by using full data sets. The parameters of interest, clearance and volume of distribution, showed excellent agreement (R2 = 0.89 and R2 = 0.86). The ceftazidime population models were described as two-compartment kslope models, relating elimination constants to renal function. The NPEM-OSS4 model was described by the equations kel = 0.06516+ (0.00708.CLCR) and V1 = 0.1773 +/- 0.0406 liter/kg where CLCR is creatinine clearance in milliliters per minute per 1.73 m2, V1 is the volume of distribution of the central compartment, and kel is the elimination rate constant. Predictive performance evaluation for 31 patients with data which were not part of the model data sets showed that the NPEM-ALL model performed best, with significantly better precision than that of the standard two-stage model (P < 0.001). Predictions with the NPEM-OSS4 model were as precise as those with the NPEM-ALL model but slightly biased (-2.2 mg/liter; P < 0.01). D-optimal monitoring strategies coupled with population modeling results in useful and cost-effective population models and will be of advantage in clinical practice, as it allows pharmacokinetic-pharmacodynamic modeling with sparse data, thus describing the relationship between ceftazidime exposure and response in the treatment of acute exacerbations in patients with cystic fibrosis.

Prospective evaluation of a dose prediction algorithm for intravenous tobramycin in adolescent and adult patients with cystic fibrosis.

The predictive performance of a new algorithm to calculate the initial daily dose of tobramycin in patients with cystic fibrosis (CF) was prospectively evaluated. Twenty-six patients with CF (15 men, 11 women, 18-45 years of age) with an acute exacerbation of their chronic pulmonary infection were treated with intravenous tobramycin. The initial dose was calculated with a previously presented algorithm. This algorithm was derived from correlation analysis performed on the adjusted daily dose guided by the determination of serum concentrations: dose (mg three times daily) = 90 + 2.13 x LBM (kg), where LBM (male) = (1.1 x body weight [BW]) - (128 x BW2/height2) and LBM (female) = (1.07 x BW) - (148 x BW2/height2). The predictive performance of this algorithm was evaluated comparing the calculated initial daily dose with the adjusted daily dose for peak and trough levels of 9-11 mg/L and 1.0 mg/L, respectively. Mean squared error and mean error were determined as reflections of precision and bias. The predictive performance of the algorithm was compared with historical data on the predictive performance of the standard equation to dose of 3.3 mg/kg body weight three times daily. The dose calculated with the algorithm proved to give peak serum concentrations in a narrower range and to have a greater precision, but bias was equal. Applying the algorithm, more patients had initial peak serum concentrations in the pre-determined range of 9-11 mg/L than when using the standard equation, so fewer dose adjustments had to be made.

Pharmacokinetics of ceftazidime in adult cystic fibrosis patients during continuous infusion and ambulatory treatment at home.

Acute exacerbations of Pseudomonas aeruginosa lung infections were treated with ceftazidime (CTZ) by continuous infusion (CI) in eight adult cystic fibrosis (CF) patients. CTZ pharmacokinetics were studied after a single dose and during CI (100 mg/kg/24 h) with a CADD-PLUS infusion pump at home for 3 weeks. Individual CTZ pharmacokinetic parameters after single-dose administration were a half-life (t1/2 beta) of 1.90 +/- 0.85 h (mean +/- SD), a volume of distribution (Vs) of 0.28 +/- 0.08 L/kg, and a total body clearance (CL) of 0.152 +/- 0.014 L/h/kg. CL during CI was 0.147 +/- 0.019 L/h/kg, equal to the CL after a single dose. CTZ clearance at the start and at the end of the treatment did not differ. The mean fraction of the dose recovered from the urine was 92.6% (range 85.6-98.5%). Renal clearance was 0.147 +/- 0.015 L/h/kg and was not influenced by the pulmonary exacerbation. The early-morning serum concentrations were significantly higher than the afternoon levels (p < 0.02). The mean CTZ serum concentration during CI was 28.7 +/- 5.0 mg/L. Clinical condition and quality of life improved significantly during and after treatment. With the pharmacokinetic population data from the single-dose study, the CTZ steady-state concentrations during CI could be predicted [precision (root mean squared prediction error) 3.1 mg/L; bias (mean prediction error) 0.4 mg/L]. This method may serve as a model in the development of CTZ continuous-infusion dosage regimens in CF home treatment.

Suggestions for the optimization of the initial tobramycin dose in adolescent and adult patients with cystic fibrosis.

Clinical pharmacokinetic data of intravenously administered tobramycin in 34 patients with cystic fibrosis (CF) were correlated with patient parameters. Patients began tobramycin therapy with 10 mg/kg/day in three divided doses. Peak and trough serum concentrations were measured. Tobramycin dose was adjusted to a 30 min postdose peak of 10 mg/L and a predose trough of 1 mg/L. Pharmacokinetic data were calculated according to a one-compartment open model and were correlated with clinical data. Tobramycin half-life and total body clearance did not correlate with age, actual body weight, lean body mass, height, or body surface area. Tobramycin volume of distribution correlated with actual body weight (p < 0.02), lean body mass (p < 0.002), height (p < 0.05), and body surface area (p < 0.01), but not with age. The required daily dose after adjustment to a peak serum concentration of 10 mg/L and a trough level of 1 mg/L correlated with lean body mass (p < 0.02) and body surface area (p < 0.05). Based on our findings, the initial daily dose of tobramycin in patients with CF should be calculated by lean body mass rather than actual body weight or body surface area. A formula is presented to calculate the initial daily dose of tobramycin in CF patients who have normal renal function. Monitoring of tobramycin serum levels remains, however, necessary.