Short-term measures of relative efficacy predict longer-term reductions in human immunodeficiency virus type 1 RNA levels following nelfinavir monotherapy.

We calculated the relative efficacy of treatment, defined as the rate of decline of virus levels in plasma during treatment relative to the rate of decline during highly potent combination therapy, in human immunodeficiency virus type 1 (HIV-1) patients treated for 56 days with different doses of the protease inhibitor nelfinavir. Relative efficacies based on the rate of decline of HIV-1 RNA levels in plasma over the first 14 to 21 days correlated with drug dose and viral load reduction by day 56. Calculation of relative treatment efficacies over the first 2 to 3 weeks of treatment can allow rapid assessment of new antiretroviral agents and dosing regimens, reducing the need to keep subjects in clinical trials on monotherapy for prolonged periods of time. Relative efficacy may also serve as a measure of treatment efficacy in patients in initiating established therapies.

A comparison of the steady-state pharmacokinetics and safety of abacavir, lamivudine, and zidovudine taken as a triple combination tablet and as abacavir plus a lamivudine-zidovudine double combination tablet by HIV-1-infected adults.

STUDY OBJECTIVE: To investigate the steady-state pharmacokinetics of a triple combination tablet containing abacavir (ABC) 300 mg, lamivudine (3TC) 150 mg, and zidovudine (ZDV) 300 mg taken twice/day, and those of ABC 300 mg twice/day plus a double combination tablet containing 3TC 150 mg and ZDV 300 mg twice/day (ABC-COM). DESIGN: Open-label, crossover study. SETTING: Two hospital-based clinical research units. PATIENTS: Twelve men infected with human immunodeficiency virus-1. INTERVENTION: Steady-state pharmacokinetics of ABC, 3TC, and ZDV were assessed after dosing with ABC-COM and the triple combination tablet. MEASUREMENTS AND MAIN RESULTS: Steady-state pharmacokinetics of ABC, 3TC, and ZDV were similar for the triple combination tablet versus ABC-COM for the following: geometric mean (GM) area under the serum concentration-time curve, ABC 6.08 versus 5.87, 3TC 5.51 versus 5.53, and ZDV 1.38 versus 1.46 microg x hr/ml; GM maximum serum concentration (Cmax-ss), ABC 3.09 versus 3.19, 3TC 1.26 versus 1.40, and ZDV 1.19 versus 1.15 microg/ml; median time to Cmax-ss, ABC 0.75 versus 0.75, 3TC 1.50 versus 1.24, and ZDV 0.75 versus 0.75 hours; and GM oral clearance, ABC 51 versus 49, 3TC 27 versus 27, and ZDV 217 versus 206 L/hour. The GM half-lives of ABC and ZDV were similar for both treatments, 1.69 versus 1.58 and 2.30 versus 2.08 hours, respectively. CONCLUSION: Steady-state pharmacokinetics of ABC, 3TC, and ZDV were similar in patients who took them as ABC-COM or as a triple combination tablet.

Abacavir/lamivudine/zidovudine as a combined formulation tablet: bioequivalence compared with each component administered concurrently and the effect of food on absorption.

A single-center, open-label, three-way crossover study was conducted in 24 healthy subjects to assess (1) the bioequivalence of a combined abacavir 300 mg/lamivudine 150 mg/zidovudine 300 mg (A/L/Z) combination tablet relative to the separate brand-name components administered simultaneously and (2) the effect of food on the bioavailability of the drugs from the combination tablet. The subjects were randomly assigned to receive each of the following three treatments, separated by a 2-day washout period: one A/L/Z combination tablet after an overnight fast, one abacavir 300 mg tablet + one lamivudine 150 mg tablet + one zidovudine 300 mg tablet sequentially after an overnight fast, or one A/L/Z combination tablet 5 minutes after completing a standardized high-fat breakfast (67 g fat, 58 g carbohydrate, and 33 g protein). Serial blood samples were collected up to 24 hours postdose for determination of abacavir, lamivudine, and zidovudine serum concentrations. Standard pharmacokinetic parameters were estimated. Treatments were considered bioequivalent if 90% confidence intervals (CI) for geometric least squares (GLS) mean ratios for abacavir, lamivudine, and zidovudine area under the serum concentration-time curve (AUC(infinity)) and maximum observed serum concentration (Cmax) fell entirely within 0.80 to 1.25 for log-transformed parameters. The combined A/L/Z tablet was bioequivalent in the extent (AUC) and rate of absorption (Cmax and time of Cmax [tmax]) to the individual brand-name drug components administered concurrently under fasted conditions. GLS ratios and 90% CI for AUC(infinity) and Cmax were 0.99 (0.96, 1.03) and 1.00 (0.90, 1.11), respectively, for abacavir; 0.95 (0.91, 0.99) and 0.90 (0.84, 0.99), respectively, for lamivudine; and 0.95 (0.89, 1.02) and 0.96 (0.80, 1.15), respectively, for zidovudine. The extent of absorption of abacavir, lamivudine, and zidovudine from the combination tablet was not altered by administration with meals, indicating that this formulation may be administered with or without food. However, food slowed the rate of absorption, delayed the tmax, and reduced the Cmax of abacavir, lamivudine, and zidovudine. These changes, which were consistent with those observed with the individual reference formulations when administered with food, were not considered clinically important. All formulations were well tolerated underfasted and fed conditions.

Population pharmacokinetics of lamivudine in adult human immunodeficiency virus-infected patients enrolled in two phase III clinical trials.

Lamivudine population pharmacokinetics were investigated by using nonlinear mixed-effect modelling (NONMEM) analysis of data from 394 human immunodeficiency virus (HIV)-infected patients treated with lamivudine (150 to 300 mg every 12 h) in two large, phase III clinical efficacy-safety trials, NUCA3001 and NUCA3002. Analyses of 1,477 serum lamivudine concentration determinations showed that population estimates for lamivudine oral clearance (CL/F; 25.1 liters/h) and volume of distribution (V/F; 128 liters) were similar to values previously reported for HIV-infected patients in phase I pharmacokinetic studies. Lamivudine CL/F was significantly influenced by the covariates creatinine clearance and weight and not affected by age, Centers for Disease Control and Prevention (CDC) classification, CD4(+) cell count, HIV type 1 (HIV-1) RNA PCR, or gender and race when CL/F was corrected for differences in patient weight. The population estimate for lamivudine V/F was not significantly influenced by the covariates gender, race, age, weight, renal function, HIV-1 RNA PCR, or CDC classification and CD4(+) cell count when creatinine clearance was included with CL/F in the model. Lamivudine disposition was significantly influenced by renal function. However, as only three patients had an estimated creatinine clearance of <60 ml/min, dosage adjustments for patients with impaired renal function should not be determined based on the population parameters derived in this analysis.

Clinical pharmacokinetics of lamivudine.

Lamivudine (3TC), the negative enantiomer of 2'-deoxy-3'-thiacytidine, is a dideoxynucleoside analogue used in combination with other agents in the treatment of human immunodeficiency virus type 1 (HIV-1) infection and as monotherapy in the treatment of hepatitis B virus (HBV) infection. Lamivudine undergoes anabolic phosphorylation by intracellular kinases to form lamivudine 5'-triphosphate, the active anabolite which prevents HIV-1 and HBV replication by competitively inhibiting viral reverse transcriptase and terminating proviral DNA chain extension. The pharmacokinetics of lamivudine are similar in patients with HIV-1 or HBV infection, and healthy volunteers. The drug is rapidly absorbed after oral administration, with maximum serum concentrations usually attained 0.5 to 1.5 hours after the dose. The absolute bioavailability is approximately 82 and 68% in adults and children, respectively. Lamivudine systemic exposure, as measured by the area under the serum drug concentration-time curve (AUC), is not altered when it is administered with food. Lamivudine is widely distributed into total body fluid, the mean apparent volume of distribution (Vd) being approximately 1.3 L/kg following intravenous administration. In pregnant women, lamivudine concentrations in maternal serum, amniotic fluid, umbilical cord and neonatal serum are comparable, indicating that the drug diffuses freely across the placenta. In postpartum women lamivudine is secreted into breast milk. The concentration of lamivudine in cerebrospinal fluid (CSF) is low to modest, being 4 to 8% of serum concentrations in adults and 9 to 17% of serum concentrations in children measured at 2 to 4 hours after the dose. In patients with normal renal function, about 5% of the parent compound is metabolised to the trans-sulphoxide metabolite, which is pharmacologically inactive. In patients with renal impairment, the amount of trans-sulphoxide metabolite recovered in the urine increases, presumably as a function of the decreased lamivudine elimination. As approximately 70% of an oral dose is eliminated renally as unchanged drug, the dose needs to be reduced in patients with renal insufficiency. Hepatic impairment does not affect the pharmacokinetics of lamivudine. Systemic clearance following single intravenous doses averages 20 to 25 L/h (approximately 0.3 L/h/kg). The dominant elimination half-life of lamivudine is approximately 5 to 7 hours, and the in vitro intracellular half-life of its active 5'-triphosphate anabolite is 10.5 to 15.5 hours and 17 to 19 hours in HIV-1 and HBV cell lines, respectively. Drug interaction studies have shown that trimethoprim increases the AUC and decreases the renal clearance of lamivudine, although lamivudine does not affect the disposition of trimethoprim. Other studies have demonstrated no significant interaction between lamivudine and zidovudine or between lamivudine and interferon-alpha-2b. There is limited potential for drug-drug interactions with compounds that are metabolised and/or highly protein bound.

Serum and cerebrospinal fluid pharmacokinetics of intravenous and oral lamivudine in human immunodeficiency virus-infected children.

We studied the pharmacokinetics of intravenously and orally administered lamivudine at six dose levels ranging from 0.5 to 10 mg/kg of body weight in 52 children with human immunodeficiency virus infection. A two-compartment model with first-order elimination from the central compartment was simultaneously fitted to the serum drug concentration-time data obtained after intravenous and oral administration. The maximal concentration at the end of the 1-h intravenous infusion and the area under the concentration-time curve after oral and intravenous administration increased proportionally with the dose. The mean clearance of lamivudine (+/- standard deviation) in the children was 0.53 +/- 0.19 liter/kg/h (229 +/- 77 ml/min/m2 of body surface area), and the mean half-lives at the distribution and elimination phases were 0.23 +/- 0.18 and 2.2 +/- 2.1 h, respectively. Clearance was age dependent when normalized to body weight but age independent when normalized to body surface area. Lamivudine was rapidly absorbed after oral administration, and 66% +/- 25% of the oral dose was absorbed. Serum lamivudine concentrations were maintained above 1 microM for >/=8 h of 24 h on the twice daily oral dosing schedule with doses of >/=2 mg/kg. The cerebrospinal fluid drug concentration measured 2 to 4 h after the dose was 12% (range, 0 to 46%) of the simultaneously measured serum drug concentration. A limited-sampling strategy was developed to estimate the area under the concentration-time curve for concentrations in serum at 2 and 6 h.

A preliminary evaluation of nelfinavir mesylate, an inhibitor of human immunodeficiency virus (HIV)-1 protease, to treat HIV infection.

A phase I/II dose-ranging open-label 28-day monotherapy study of the safety, pharmacokinetics, and antiviral activity of nelfinavir mesylate (Viracept), an inhibitor of human immunodeficiency virus (HIV)-1 protease, was done in 65 HIV-1-infected subjects. After 28 days, 54 responding subjects entered an open-label extension that allowed for the addition of nucleoside inhibitors of reverse transcriptase and dose escalation to maintain durability. The drug was well-tolerated and demonstrated robust antiviral activity, with demonstrable superiority of the 750 mg and 1000 mg three times daily regimens. Thirty subjects who continued to receive therapy at 12 months attained a persistent 1.6 log10 reduction in HIV RNA, accompanied by a mean increase in CD4 cells of 180-200/mm3. Studies of viral genotype and phenotype after virus rebound revealed that the initial active site mutation allowing for nelfinavir resistance is mediated by a unique amino acid substitution in the HIV-1 protease D30N, which does not confer in vitro phenotypic cross-resistance to the currently available protease inhibitors.

Pharmacokinetics of lamivudine in human immunodeficiency virus-infected patients with renal dysfunction.

The purpose of this study was to determine the safety and pharmacokinetics of lamivudine (3TC), a nucleoside analog that has shown potent in vitro and recent in vivo activity against human immunodeficiency virus. Sixteen human immunodeficiency virus-infected patients, six with normal renal function (creatinine clearance [CLCR], > or = 60 ml/min), four with moderate renal impairment (CLCR, 10 to 40 ml/min), and six with severe renal impairment (CLCR, < 10 ml/min), were enrolled in the study. After an overnight fast, patients were administered 300 mg of 3TC orally. Blood was obtained before 3TC administration and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 32, 40, and 48 h afterward. Timed urine collections were performed for patients able to produce urine. Serum and urine were assayed for 3TC by reverse-phase high-performance liquid chromatography with UV detection. Pharmacokinetic parameters were calculated by using standard noncompartmental techniques. The peak concentration of 3TC increased with decreasing renal function; geometric means were 2,524, 3,538, and 5,684 ng/ml for patients with normal renal function, moderate renal impairment, and severe renal impairment, respectively. The terminal half-life also increased with decreasing renal function; geometric means were 11.5, 14.1, and 20.7 h for patients with normal renal function, moderate renal impairment, and severe renal impairment, respectively. Both oral and renal clearances were linearly correlated with CLCR. A 300-mg dose of 3TC was well tolerated by all three patient groups. The pharmacokinetics of 3TC is profoundly affected by impaired renal function. Dosage adjustment, by either dose reduction or lengthening of the dosing interval, is warranted.

Pharmacokinetics of lamivudine administered alone and with trimethoprim-sulfamethoxazole.

OBJECTIVE: To determine the effect of multiple dosing of combined sulfamethoxazole and trimethoprim on the single-dose pharmacokinetics of lamivudine. METHODS: Fourteen subjects with human immunodeficiency virus who had CD4+ cells > or = 200/mm3 received two single doses of 300 mg lamivudine, separated by 7 to 14 days, in a randomized two-day crossover study. Treatment consisted of lamivudine alone versus trimethoprim-sulfamethoxazole (160/180 mg) daily on days 1 through 4 followed by lamivudine plus trimethoprim-sulfamethoxazole on day 5. Blood and urine were collected over 24 to 32 hours to determine lamivudine, trimethoprim, sulfamethoxazole, and N-4-acetylsulfamethoxazole concentrations. RESULTS: Coadministration of a single dose of lamivudine and trimethoprim-sulfamethoxazole after daily dosing for 5 days altered the pharmacokinetics of lamivudine. A 43% increase in area under the concentration-time curve (AUC infinity) and a 35% decrease in renal clearance (CLR) were observed when lamivudine was coadministered with trimethoprim-sulfamethoxazole compared with lamivudine alone. The geometric least-squares trimethoprim-sulfamethoxazole were as follows: AUC infinity, 10,124 (9,432-10,866) and 14,448 (13,461-15,508) ng . hr/ml, respectively; CLR, 16.6 (14.1-19.4) and 10.8 (9.5-12.6) L/hr, respectively. Coadministration did not significantly alter the pharmacokinetics of trimethoprim or sulfamethoxazole. CONCLUSIONS: Coadministration of lamivudine with trimethoprim-sulfamethoxazole resulted in an increased AUC infinity and a decreased CLR of lamivudine. However, given the favorable safety profile of lamivudine, it is unlikely that this interaction will result in a significant increase in concentration-related toxicity at the doses studied.

Pharmacokinetics, absolute bioavailability, and absorption characteristics of lamivudine.

Lamivudine is a novel cytosine nucleoside analog, reverse transcriptase inhibitor that has shown activity against human immunodeficiency virus (HIV) types 1 and 2 and hepatitis B virus in vitro. This study was conducted to compare the absolute bioavailability, pharmacokinetics, and absorption characteristics of oral solution, 100-mg capsule, and 100-mg tablet formulations of lamivudine with those of intravenous lamivudine. Twelve patients with HIV were enrolled in a single-center, randomized, open-label, four-way cross-over study. Treatment arms consisted of 100 mg intravenous lamivudine (administered over 1 hour), 100 mg oral lamivudine (1 mg/mL), a 100-mg capsule, and a 100-mg tablet, each followed by a 3- to 14-day washout period. Serial blood samples over 24 hours were obtained after each dose administration. Serum concentration data were analyzed to determine pharmacokinetic parameter estimates including area under the curve (AUC), terminal half-life (t1/2), mean residence time (MRT) for each formulation, systemic clearance, oral clearance, and apparent volume of distribution (Vd). Absolute bioavailability and in vivo mean absorption time (MAT) and mean dissolution time (MDT) were calculated for the oral formulations. Deconvolution techniques were used to calculate the input rate for the oral solution, capsule, and tablet. The two one-sided t test was used to determine bioequivalency among oral formulations with respect to logarithmic transformed estimates of AUC and maximum peak concentration (Cmax). Mean (CV) systemic clearance and Vdss after intravenous administration of lamivudine were 22.6 L/h (15%) and 99 L (28%), respectively; mean t1/2 ranged from 8.41 to 9.11 hours for all formulations; and MRT ranged from 4.42 to 5.77 hours for all formulations. Mean absolute bioavailability ranged from 86% to 88% for the oral solution, capsule, and tablet. All oral formulations were considered bioequivalent for AUC and Cmax. The MAT was 1.32 hour for the oral solution, and MDT was 0.03 and -0.11 hours for the capsule and the oral solution, respectively. The oral formulations of lamivudine examined in this study demonstrated acceptable bioavailability for oral administration. The solid oral formulations (capsule and tablet) show rapid dissolution properties with an absorption rate similar to or exceeding those observed with the oral solution. This suggests that dissolution is not an important factor for the rate of absorption of lamivudine. The use of deconvolution techniques using PCDCON provides valuable insight into the absorption characteristics of lamivudine.

Population differences in ganciclovir clearance as determined by nonlinear mixed-effects modelling.

We examined the pharmacokinetics of ganciclovir in different populations of cytomegalovirus (CMV)-infected patients through the use of nonlinear mixed-effects modelling. As expected, patient weight and estimated creatinine clearance were shown to be important covariates in the serum ganciclovir clearance. Unexpectedly, major differences in ganciclovir clearance between different populations of patients were found. Human immunodeficiency virus (HIV)-infected patients with CMV retinitis cleared ganciclovir 41% faster than HIV-infected patients only shedding CMV into the urine. Solid-organ transplant patients had a serum clearance one-fourth that of HIV-infected patients, even with correction for creatinine clearance. These findings require prospective validation and may have important implications for ganciclovir dosing in different populations of CMV-infected patients.

Impact of bioavailability on determination of the maximal tolerated dose of 2',3'-dideoxyinosine in phase I trials.

The objective of this study was to determine the population pharmacokinetic parameters and the extent of absorption of 2',3'-dideoxyinosine, a nucleoside analog with activity against human immunodeficiency virus in vitro and in vivo, after oral and intravenous administration through the use of NON-linear Mixed Effects Modeling. The data were drawn from the pharmacokinetics section of an open-label, multicenter phase I study. One center administered ddI on a once-daily schedule. The other centers administered the drug once every 12 h. Drug was administered intravenously, and the plasma concentration-time profile was determined. Patients were then given the drug orally at twice the dose used in the intravenous portion of the study, and the pharmacokinetic profile was again determined. A 40-fold range of doses was examined. Forty-six human immunodeficiency virus-infected patients were studied. Concentrations in plasma were determined by high-pressure liquid chromatography. Clearance of the drug from plasma was 47.7 liters/h/70 kg of body weight. The terminal half-life was 1.4 h. The volume of distribution in the central compartment was 18.8 liters/70 kg. Absorption was rapid, with an absorption half-life of 0.52 h. Bioavailability with once-daily administration was 27%. For twice-daily administration, bioavailability rose to 36%. This difference was significant (P much less than 0.01). For doses of less than or equal to 5.1 mg/kg given every 12 h (10.2 mg/kg/day), bioavailability was 41%. We conclude that once-daily administration results in lower mean bioavailability, probably because of a saturation of the absorption process similar to that seen with acyclovir. This difference in bioavailability on the basis of the administration schedule explains the different short-term maximal tolerated doses identified in phase I trials of this agent.

Relationship between dideoxyinosine exposure, CD4 counts, and p24 antigen levels in human immunodeficiency virus infection. A phase I trial.

OBJECTIVE: To determine the relation between exposure to dideoxyinosine (ddl) and increased CD4 cell counts and suppression of serum p24 antigen in patients infected with the human immunodeficiency virus (HIV). DESIGN: Open-label, phase I study. SETTING: Two university hospitals. Patients were studied in both inpatient and outpatient settings. PATIENTS: Of 36 HIV-infected patients enrolled, 18 had adequate pharmacokinetic information for analysis. INTERVENTION: Dideoxyinosine was administered intravenously every 12 hours for 2 weeks. Patients were switched to oral administration at twice the intravenous dose. Pharmacokinetic profiles were obtained twice during each period. A 40-fold range of dose was examined. MEASUREMENTS: CD4-positive T-lymphocyte counts and serum p24 antigen levels were determined. Plasma area under the ddl concentration-time curve was determined for a single dose and at steady state. RESULTS: Increases in CD4-positive T-lymphocyte counts were independent of ddl exposure and were proportional to the starting CD4 count. Suppression of circulating p24 antigen was influenced by cumulative exposure to ddl and was statistically significant. CONCLUSIONS: The CD4-positive T-lymphocyte count increased at low ddl concentrations or exposures; the extent of this increase was directly proportional to the patient's CD4 count at the start of therapy. Suppression of p24 antigen was related to cumulative exposure to ddl. Therapeutic responses can probably be obtained with ddl, while minimizing long-term toxicity, using daily doses of 10 mg/kg body weight, or less.

Use of nonlinear, mixed-effects modeling for population analysis of ofloxacin: effects of age on oral drug pharmacokinetics.

To compare the effect of age on pharmacokinetics of orally administered ofloxacin, two separate studies were reanalyzed using mixed-effect modeling with the program NONMEM. Subjects were male volunteers, 36 age 65 years or greater and 24 age 18-40 years. The younger group received three 100-mg tablets and the older group received two 200-mg tablets of ofloxacin. Serial blood samples obtained throughout dosing were assayed for drug concentrations using high-performance liquid chromatography. A pharmacostatistical model was developed for the data using mixed-effect modeling with NONMEM. A one-compartment open model with first-order absorption, which included the covariables weight and age, best fit the data. Mean (SE) population values were clearance/F 0.219 (0.009) L/hr/kg, volume of distribution/F 1.50 (0.071) L/kg, and absorption rate constant 2.26 (0.048) hr-1. Older subjects had a 29% lower clearance and 13% lower volume of distribution then the younger subjects.

Altered pharmacokinetics in the elderly.

Physiologic changes that occur in the aging process may directly affect drug pharmacokinetics. Alteration of the pharmacokinetics of these drugs in the elderly may necessitate adjustment of drug dosages to prevent toxicity or inadequate therapy. Whereas clinical tests to measure renal function may be used quantitatively to prospectively individualize a drug dosage to an elderly patient, tests for hepatic function do not correlate as well with changes in hepatic drug metabolism. Despite these limitations, recognition of the relationship between physiologic changes and drug pharmacokinetics is important to better prescribe the correct dose in the elderly population.

Ciprofloxacin pharmacokinetics in critically ill trauma patients.

The steady-state pharmacokinetics of ciprofloxacin 200 mg intravenously every 12 hours was examined in 10 critically ill trauma patients. The mean parameter estimates for total clearance, renal clearance, non-renal clearance, and volume of distribution were 30.08 liters/hour/1.73 m2, 16.62 liters/hour/1.73 m2, 13.46 liters/hour/1.73 m2, and 2.10 liters/kg. Although the mean values were similar to those previously reported, significant individual differences were observed, with the coefficient of variation ranging from 41 to 61 percent. Non-renal clearance appeared to have a bimodal distribution. The dosage studied appeared to provide adequate serum concentration profiles to treat most pathogens found in infected trauma patients. However, the use of higher doses and more frequent dosing may be required to treat patients with Staphylococcus aureus and Pseudomonas aeruginosa infections.

Prospective use of optimal sampling theory: steady-state ciprofloxacin pharmacokinetics in critically ill trauma patients.

We examined the use of optimal sampling theory to determine a sparse sampling design to estimate pharmacokinetic parameters of ciprofloxacin in patients who had sustained trauma. Two serum sampling strategies, consisting of six sampling times each, were derived on the basis of the patient's renal function (patients with creatinine clearance greater than or equal to 6 L/hr/1.73 m2 and patients with creatinine clearances less than 6 L/hr/1.73 m2). Two additional serum samples were obtained for other aspects to the study. A timed urine collection was also obtained. Pharmacokinetic parameter estimates were determined by comodeling the serum and urine data with a three-compartment open model (parameterized as microconstants) with a bayesian algorithm and by noncompartmental analysis. Bayesian-derived parameter estimates were total body clearance of drug from plasma, 29.8 L/hr/1.73 m2; renal clearance, 17.0 L/hr/1.73 m2; and nonrenal clearance, 12.7 L/hr/1.73 m2 and were not significantly different from noncompartmentally derived parameters (p = 0.80, p = 0.65 and p = 0.333, respectively). The study demonstrates the use of optimal sampling theory to determine an informative yet relatively sparse sampling strategy for a drug with a complex pharmacokinetic model.

Phenytoin dosage predictions in paediatric patients.

Phenytoin dosing in paediatric patients is complicated both by alterations in patient requirements due to growth and maturation changes and by the capacity-limited characteristics of phenytoin metabolism. This study examines 2 pharmacokinetic methods to adjust phenytoin dosage based on a single dosing-rate/steady-state serum phenytoin concentration pair. A Bayesian forecaster and a fixed parameter [rate of metabolism (Vmax)] method were examined with previously published sets of a priori parameter estimates. The fixed Vmax method was utilised with the parameter derived from native Japanese (method 1), US Caucasian (method 2) and European (method 3) patients. The Bayesian forecaster used a priori parameter estimates obtained from native Japanese (method 4) and European (method 5) patients. Each method was examined retrospectively in 34 paediatric patients with a total of 48 predictions possible. Measures of absolute predictability, bias (mean error, % dose) and precision (root mean squared error, % dose), were -3.58/12.2, -1.51/12.2, 4.06/9.96, -4.38/13.2, and -3.10/11.5, for methods 1, 2, 3, 4 and 5, respectively. There was no significant difference among the 5 methods. However, the Bayesian algorithm tended to be more robust over a broad range of situations, providing predictions in all cases. The fixed Vmax methods could not provide predictions in every case. Finally, all methods had a significant number of overpredictions of dosage. Poorer results were observed when prediction of steady-state serum concentrations were performed, partly due to the retrospective nature of the study. We conclude that close monitoring of patients, regardless of the method chosen to adjust dosage, is recommended.