Comparison of population pharmacokinetic models for gentamicin in spinal cord-injured and able-bodied patients.

Population pharmacokinetic models forgentamicin weredeveloped byusing dataobtained from29spinal cord-injured patients and11able-bodied control patients. Withaone-compartment model, thepopulation parameters wereclearance (CL),volumeofdistribution (K,andtheir associated variances. Parameter estimates werefoundbyusing thecomputer program NPEM andbythestandard two-stage (STS) method. NPEM usesanonparametric approach incorporating theexpectation maximization algorithm toevaluate a joint probability density function at900intersections overabivariate grid. Incontrast, theSTSmethod requires conventional assumptions ofnormality fortheunderlying distributions. ForNPEM,themeanCLwas 97.6mI/h/kg ofbodyweight (coefficient ofvariation, 33.0%inthespinal cord-injured patients and67.8ml/h/kg + 28.2%intheable-bodied patients; themeanVwas0.31liter/kg ±32.3%inthespinal cord-injured patients and0.23liter/kg + 15.8%intheable-bodied patients. ForSTS,themeanCLwas101.0 ml/h/kg + 37.5%in thespinal cord-injured patients and65.0ml/h/kg + 33.8%intheable-bodied patients; themeanVwas0.29 liter/kg ± 34.0%inthespinal cord-injured patients and0.21liter/kg ± 21.0%intheable-bodied patients. Although themeansandvariances foundbyNPEM andtheSTSmethod weresimilar, theNPEM analysis revealed that thedistributions ofCLandV,evenafter they werelinked toweight, werepositively skewed and kurtotic. Thecumulative distribution functions forCL(P< 0.001) andV(P< 0.001) inspinal cord-injured patients weredifferent fromthose inable-bodied patients. Unique population models arerequired fortheinitial dosage selection forspinal cord-injured patients. Future approaches fordeveloping population models should allow thelinkage ofstructural parameters tomultiple patient covariates. Population pharmacokinetic methods areusedtostudy pharmacokinetic processes byanalyzing pooled datasampledfromsomeunderlying population ofinterest (1,5,12, 15,19,28). Population approaches provide meanparameter estimates andallow variances tobepartitioned into withinindividual andbetween-individual components. Inaddition, population approaches allow pharmacokinetic parameters to belinked toinformative covariates, andthis mayfurther reducethevariance termsinthemodels. Examples of informative covariates areage,gender, ethnicity, bodysize, health-disease status ormarkers, environmental exposures, andgenetic characteristics. Properly constructed population pharmacokinetic modelsareuseful forselecting rational dosing regimens ofdrugs forindividual patients. Thestandard two-stage (STS) methodprovides estimates ofpopulation parameters instages (25, 27). Inthefirst stage, ordinary least-squares regression parameters areestimated fromdatafromeachindividual. Inthesecond stage, population parameters areestimated bypooling theindividual estimates. Thismethod, like thecomputer program NONMEM, whichutilizes extended least squares toformmixed-effect population models (1), requires theassumption thattheunderlying population distributions arenormal orwill benormal after suitable transformations (19). Nonparametric, maximum-likelihood approaches topopulation models havealso beendeveloped previously (15, 18). Thesemethods donotrequire theparametric assumptions of