Alteration in cytochrome P450 3A4 activity as measured by a urine cortisol assay in HIV-1-infected pregnant women and relationship to antiretroviral pharmacokinetics.

OBJECTIVES: Pregnancy results in physiological changes altering the pharmacokinetics of drugs metabolized by cytochrome P450 3A4 (CYP3A4). The urinary ratio of 6-ß hydroxycortisol to cortisol (6ßHF : F) is a marker of CYP3A4 induction. We sought to evaluate its change in antiretroviral (ARV)-treated HIV-1-infected women and to relate this change to ARV pharmacokinetics. METHODS: Women receiving various ARVs had pharmacokinetic evaluations during the third trimester of pregnancy (>30 weeks) and postpartum with determination of 6ßHF : F carried out on the same days. The Wilcoxon signed rank test was used to compare the ratio antepartum to postpartum. The relationship between the change in ratio and the change in pharmacokinetics was analysed using Kendall's tau. RESULTS: 6ßHF : F ratios were available for 107 women antepartum, with 54 having postpartum values. The ratio was higher antepartum (P=0.033) (median comparison 1.35; 95% confidence interval 1.01, 1.81). For 71 women taking a protease inhibitor (PI), the antepartum vs. postpartum 6ßHF : F comparison was marginally significant (P=0.058). When the change in the 6ßHF : F ratio was related to the change in the dose-adjusted ARV area under the plasma concentration vs. time curve (AUC) between antepartum and postpartum, the 35 subjects in the lopinavir/ritonavir (LPV/r) arms demonstrated an inverse relationship (P=0.125), albeit this correlation did not reach statistical significance. CONCLUSIONS: A 35% increase in the urinary 6ßHF : F ratio was measured during late pregnancy compared with postpartum, indicating that CYP3A induction occurs during pregnancy. The trend towards an inverse relationship between the change in the 6ßHF : F ratio and the change in the LPV AUC antepartum vs. postpartum suggests that CYP3A induction may be one mechanism behind altered LPV exposure during pregnancy.

Pharmacokinetics of tenofovir during pregnancy and postpartum.

OBJECTIVES: Tenofovir disoproxil fumarate (TDF) is increasingly used in the highly active antiretroviral therapy (HAART) regimens of pregnant women, but limited data exist on the pregnancy pharmacokinetics of chronically dosed TDF. This study described tenofovir pharmacokinetics during pregnancy and postpartum. METHODS: International Maternal Pediatric and Adolescent AIDS Clinical Trials (IMPAACT) P1026s is a prospective, nonblinded pharmacokinetic study of HIV-infected pregnant women that included a cohort receiving 300 mg TDF once daily. Steady-state 24-hour pharmacokinetic profiles were measured at the second and third trimesters, postpartum, and in maternal and umbilical cord samples collected at delivery. Tenofovir was measured by liquid chromatography-mass spectrometry (LC-MS). The target area under the concentration versus time curve from time 0 to 24 h post dose (AUC) was ≥ 1.99 µg h/mL (nonpregnant historical control 10th percentile). RESULTS: The median tenofovir AUC was decreased during the second (1.9 µg h/mL) and third (2.4 µg h/mL; P = 0.005) trimesters versus postpartum (3.0 µg h/mL). Tenofovir AUC exceeded the target for two of four women (50%) in the second trimester, 27 of 37 women [73%; 95% confidence interval (CI) 56%, 86%] in the third trimester, and 27 of 32 women (84%; 95% CI 67%, 95%) postpartum (P > 0.05). Median second/third-trimester troughs were lower (39/54 ng/mL) than postpartum (61 ng/mL). Median third-trimester weight was greater for subjects below the target AUC versus those above the target (97.9 versus 74.2 kg, respectively; P = 0.006). The median ratio of cord blood to maternal concentrations was 0.88. No infants were HIV infected. CONCLUSIONS: This study found lower tenofovir AUC and troughs during pregnancy. Transplacental passage with chronic TDF use during pregnancy was high. Standard TDF doses appear to be appropriate for most HIV-infected pregnant women but therapeutic drug monitoring with dose adjustment should be considered in pregnant women with high weight (> 90 kg) or inadequate HIV RNA response.

Lopinavir protein binding in HIV-1-infected pregnant women.

BACKGROUND: Pregnancy may alter protein binding (PB) of highly bound protease inhibitors due to changes in plasma concentrations of albumin and alpha-1 acid glycoprotein (AAG). Small changes in PB can greatly impact the fraction of drug unbound (FU) exerting pharmacological effect. We report lopinavir (LPV) PB during third trimester (antepartum, AP) compared to > or =1.7 weeks postpartum (PP) to determine if FU changes compensate for reduced total concentrations reported previously. METHODS: P1026s enrolled women receiving LPV/ritonavir, soft gel capsules 400/100 mg or 533/133 mg twice daily. LPV FU, albumin and AAG were determined AP and PP. RESULTS: AP/PP samples were available from 29/25 women respectively with all but one woman receiving the same dose AP/PP. LPV FU was increased 18% AP vs. PP (mean 0.96+/-0.16% AP vs. 0.82+/-0.21% PP, P=0.001). Mean protein concentrations were reduced AP (AAG=477 mg/L; albumin=3.28 mg/dL) vs. PP (AAG=1007 mg/L; albumin=3.85 mg/dL) (P<0.0001 for each comparison). AAG concentration correlated with LPV binding. Total LPV concentration did not correlate with LPV FU AP or PP. However, higher LPV concentration PP was associated with reduced PB and higher FU after adjustment for AAG. CONCLUSIONS: LPV FU was higher and AAG lower AP vs. PP. The 18% increase in LPV FU AP is smaller than the reduction in total LPV concentration reported previously and is not of sufficient magnitude to eliminate the need for an increased dose during pregnancy.

Population pharmacokinetics of vancomycin in adult and geriatric patients: comparison of eleven approaches.

PURPOSE: A vancomycin population pharmacokinetic prediction model for adult and elderly patients was developed using NONMEM. The predictability of the model was studied and compared with ten other models. METHODS: Data were collected from routine care of 141 subjects. NONMEM was used to derive a population model. After internal evaluation using the bootstrap technique, external validation was studied using an independent dataset that consisted of 95 subjects; a statistical comparison of precision and bias was conducted. RESULTS: A two-compartment open model was derived with body weight, age, and CLcr as covariates. The bootstrap process showed stability of the model. A comparison of subjects older and younger than 65 years found that the older group had a mean clearance of 2.24 (+/- 1.2) l/h compared to 4.03 (+/- 1.7) l/h, and a peripheral volume of 43.7 (+/- 5.1) l compared to 28.4 (+/- 5.3) l compared to younger patients. These values were modeled using CLcr in the clearance equation and Vd as a function of age. The eleven models studied showed a bias in predicting serum concentrations from the test database that ranged from 0.35 mg/l to -5.93 mg/l. Precision ranged from 4.53 mg/l to 8.05 mg/l. Our method ranked in fourth place overall and when compared statistically its bias was different from the method that ranked in second place by -1.45 (95% CI -2.46, -0.42; p = 0.005), and different from all the methods that ranked worse. The only difference in precision was with the method that ranked in eleventh place with a relative precision of 0.49 (95% CI 0.27, 0.70; p < 0.001). CONCLUSIONS: A two-compartment open model fitted the data with weight, age, and CLcr as covariates. The derived method ranked in fourth place overall. The two-compartment nature of two of the equations studied did not provide an advantage. A future study with more data in the distribution phase could provide a model with better predictability.

Pharmacokinetics of new 625 mg nelfinavir formulation during pregnancy and postpartum.

OBJECTIVES: Our objective was to evaluate the pharmacokinetics of nelfinavir (NFV) (625 mg tablets) 1250 mg twice daily during pregnancy and postpartum. METHODS: The participants were HIV-1-infected pregnant women enrolled in P1026s and receiving NFV (625 mg tablets) 1250 mg twice daily as part of routine clinical care. Intensive steady-state 12-h NFV pharmacokinetic profiles were performed during pregnancy and postpartum. The target NFV area under the plasma concentration-time curve (AUC(0-12)) was >or=10th percentile NFV AUC(0-12) in non-pregnant historical controls (18.5 microg h/mL). RESULTS: Of 27 patients receiving NFV, pharmacokinetic data were available for four (second trimester), 27 (third trimester) and 22 (postpartum) patients. The NFV maximum concentration (C(max)), 12-h post-dose concentration (C(12)) and AUC(0-12) were significantly lower during the third trimester compared to postpartum (P

Rimantadine pharmacokinetics in healthy subjects and patients with end-stage renal failure.

The single-dose (two 100 mg doses) pharmacokinetics of rimantadine hydrochloride were compared in eight patients with end-stage renal disease who were on hemodialysis and seven age-matched healthy subjects. Plasma and urine rimantadine concentrations were determined by a GC/MS method. The plasma half-life (43.6 vs 27.5 hours) and AUC (9.9 +/- 2.1 vs 6.0 +/- 1.6 micrograms.hr/ml) were significantly (p less than 0.05) increased in the patient population. No significant differences were noted in the maximum rimantadine concentration, time of maximum concentration, or apparent volume of distribution. Urinary excretion of unchanged rimantadine accounted for 16% of the dose in the healthy subjects. Hemodialysis did not appreciably remove rimantadine. These findings suggest that rimantadine dosage may need to be reduced in patients with end-stage renal disease but supplemental doses on dialysis days are not required.

Factors determining maintenance of sinus rhythm after chronic atrial fibrillation with left atrial dilatation.

Successful therapy of atrial fibrillation (AF) has been reportedly influenced by a variety of factors including patient age, type of underlying heart disease, duration of arrhythmia, left ventricular function and left atrial (LA) size. To determine which of these factors are associated with maintenance of sinus rhythm after conversion, 43 patients with symptomatic chronic AF in the setting of a dilated left atrium (greater than or equal to 45 mm, range 45 to 78) were followed for at least 6 months after the return of sinus rhythm. Class IA drugs, IC drugs or amiodarone were used for therapy. Life table analysis showed sinus rhythm to be maintained in 81% for 6 months, 79% for 12 months and 60% for 24 months. Factors positively associated with success were conversion with drug therapy alone, duration of chronic AF less than or equal to 1 year, absence of mitral valve disease and LA dimension less than or equal to 60 mm (all p less than 0.05). Patient age, left ventricular function and presence of coronary disease were not associated with outcome. Thus, patients with moderate LA dilatation (45 to 60 mm) and a short duration of chronic AF can often be maintained in sinus rhythm, especially if they convert with pharmacologic intervention alone.

Intravenous gamma-globulin treatment and retreatment in Kawasaki disease. US/Canadian Kawasaki Syndrome Study Group.

OBJECTIVE: To determine the prevalence and outcome of intravenous gamma-globulin (IVIG) retreatment in patients with Kawasaki disease (KD). METHOD: Multicenter, retrospective survey of all children with KD evaluated at nine clinical centers across North America during a 15-month period. RESULTS: Data were available for 378 patients. At 48 h after completion of the initial IVIG infusion, 50 patients (13.2%) remained febrile, 29 (58.0%) of whom were retreated with IVIG, including 4 (13.8%) with coronary artery abnormalities before their first IVIG infusion. Among 25 retreated patients with a normal baseline echocardiogram, 5 (20.0%) developed coronary abnormalities and were termed "treatment failures." Among the 323 patients with a normal baseline echocardiogram, only 9 (2.8%) were treatment failures; treatment failure occurred in 4 of 282 (1.4%) patients who became afebrile post-IVIG and in 5 of 41 (12.2%) patients with persistent or recrudescent fever after their first course of IVIG therapy (P=0.002). CONCLUSIONS: The overall prevalence of new coronary abnormalities in KD patients treated with IVIG and aspirin remains low. Persistent or recrudescent fever after the first course of IVIG was associated with an increased risk of treatment failure (P=0.002). IVIG retreatment in patients who remain febrile after the first course of IVIG is now common (58.0%), although the efficacy of this practice requires assessment with a randomized trial.

Pharmacokinetics of nelfinavir in human immunodeficiency virus-infected infants.

BACKGROUND: Nelfinavir dosed at approximately 20 to 30 mg/kg three times a day (TID) in older children provides exposure similar to 750 mg TID in adults. However, the pharmacokinetics (PK) of nelfinavir in infants who are < 2 years of age is not well-described. The objective of this study was to determine the pharmacokinetics of nelfinavir in infants < 2 years of age. METHODS: Nelfinavir concentrations were evaluated in 22 HIV-infected infants between 15 days and 2 years of age receiving nelfinavir as part of Pediatric ACTG Study 356. Nelfinavir therapy was initiated at approximately 25 mg/kg TID (n = 18) or approximately 55 mg/kg twice a day (n = 4) and given in combination with nevirapine, stavudine and lamivudine. PK samples were obtained predose and 1.5 and 4 h postdose at approximately 6-month intervals. Eight infants (all < or = 3 months of age) also had intensive PK samples collected at Week 1. RESULTS: The median apparent clearance in the infants with intensive pharmacokinetic sampling was 2.7 liters/h/kg (range, 1.8 to > or = 10) and was similar between twice a day and TID dosing cohorts. Overall nelfinavir concentrations at all collection times were lower in these infants than previously reported in older pediatric patients. CONCLUSIONS: Nelfinavir concentrations in infants are highly variable and lower than those seen in adult or older pediatric populations receiving labeled dosing. Therefore it is necessary to further evaluate nelfinavir safety, effectiveness and pharmacokinetics at higher doses than used among other pediatric populations.

Single dose pharmacokinetics of pleconaril in neonates. Pediatric Pharmacology Research Unit Network.

BACKGROUND: Pleconaril is an orally active, broad spectrum antipicornaviral agent with activity against nonpolio enteroviruses. Pleconaril phamacokinetics was evaluated in 16 neonates (16.4 +/- 8.7 days postnatal age) with suspected enteroviral infection. METHODS: Pleconaril (5 or 7.5 mg/kg) was administered orally to study subjects and plasma pleconaril concentrations quantified from serial blood samples obtained during 24 h after a single oral dose by gas chromatography with electrochemical detection. Pharmacokinetic parameter estimates were determined by noncompartmental methods and compared between doses and with similar data obtained from a previous study of pleconaril disposition in children (n = 18, 2 to 12 years). RESULTS: Pleconaril was well-tolerated in all neonates without discernible adverse events. Comparison between the 5.0- and 7.5-mg/kg doses revealed no significant differences in peak plasma concentration (Cmax 686.7 vs. 617.1 ng/ml), elimination half-life (t 1/2; 4.6 vs. 6.6 h), area under the plasma concentration vs. time curve (AUC; 5162.6 vs. 5523.9 ng/ml/h), apparent steady state volume of distribution (V(dss)/F; 9.3 vs. 17.1 liters/ kg) and apparent oral clearance (Cl/F; 1.3 vs. 1.7 liters/h/kg). In addition, no correlation was observed between postconceptional age and AUC, V(dss)/F, t 1/2 or Cl/F for pleconaril. Comparison of pleconaril pharmacokinetics between neonates and children suggested a significant difference in V(dss)/F (9.3 vs. 4.7 liters/kg), dose-normalized Cmax, (686.7 vs. 1272.5 ng(ml) and AUC (5125.6 vs. 8131.2 ng/ml/h). In contrast, the mean elimination t 1/2 between neonates and children was not appreciably different. CONCLUSIONS: The apparent age-dependent differences in the pharmacokinetics of pleconaril may in part be related to increased bioavailability of the drug in older children and adults than in neonates. Our data appear to support the use of a 5.0-mg/kg dose given every 8 to 12 h in future studies of pleconaril in neonatal patients with enteroviral infection.

Cerebrospinal fluid profile in patients with acute Kawasaki disease.

BACKGROUND: Kawasaki disease (KD) is an acute vasculitis of infancy and early childhood for which there is currently no diagnostic test. The clinical presentation of KD may initially resemble other infectious diseases, including bacterial or viral meningitis. For this reason lumbar puncture (LP) is sometimes performed during the evaluation of these patients. To understand the range of cerebrospinal fluid (CSF) changes that may be associated with acute KD, a retrospective review of unselected KD patients from three pediatric centers was performed. METHODS: Retrospective chart review was performed on KD patients evaluated during the first 10 days of illness who had an LP performed before the administration of intravenous gamma-globulin. RESULTS: During the 6.5-year study period, 46 KD patients underwent LP as part of their clinical evaluation. Of these patients 18 (39.1%) had CSF pleocytosis, 1 (2.2%) had a CSF glucose <45 mg/dl and 8 (17.4%) had an elevated CSF protein. Of the patients with CSF pleocytosis, the median white blood cell count was 22.5 cells (range, 7 to 320 cells), with a median of 6.0% neutrophils (range, 0 to 79%) and 91.5% mononuclear cells (range, 11 to 100%). CONCLUSIONS: In the present series approximately one-third of KD patients who underwent an LP had CSF pleocytosis with a mononuclear cell predominance. No patient had significant hypoglycorrhachia, and elevation of the CSF protein was uncommon. CSF abnormalities were similar between US and Japanese KD patients. The basis for the CSF pleocytosis in acute KD patients remains unknown.

Clinical and electrophysiologic effects of flecainide in patients with refractory ventricular tachycardia.

The electrophysiologic effects and antiarrhythmic efficacy of flecainide were evaluated by electrophysiologic study (EPS) in 20 patients with ventricular tachycardia (VT) refractory to an average 2.9 drugs. In 19 patients EPSs were performed with patients not receiving antiarrhythmic medications and receiving oral flecainide therapy at steady state (mean dose, 235 +/- 67 mg/day). Flecainide significantly increased the QRS complex duration (27%, P less than .001), PR interval (17%, P less than .001), and right ventricular effective refractory periods 8.5% and 21.1% (P less than .01) for the first and second extrastimuli, respectively. During baseline EPS, 17 patients were induced into VT and two were noninducible. Flecainide prevented EPS-induced VT in five patients and the induced VT became slow and hemodynamically stable in three. Two patients who failed flecainide monotherapy were induced into slow hemodynamically stable VT with flecainide in combination with amiodarone. The two noninducible patients, during baseline EPS, had suppression of spontaneous VT with flecainide. Overall, 13 of 20 patients received flecainide either alone or in combination with amiodarone for chronic therapy. Side effects encountered during the study consisted of blurred vision, dizziness, weakness, lethargy, nausea, worsened heart failure and bradyarrhythmias. After a mean 9-month follow-up (3 to 16 months) nine patients remain on flecainide therapy. There were three recurrences of slow, hemodynamically stable VT and no episodes of sudden death. Low-dose flecainide, either alone or in combination with other agents, is effective therapy for certain patients with refractory VT but heart failure remains a significant concern in patients with depressed left ventricular function.

Clinical pharmacokinetics of controlled-release disopyramide in patients with cardiac arrhythmias.

UNLABELLED: The pharmacokinetics of the controlled-release preparation of disopyramide phosphate (Norpace CR, Searle Laboratories, Chicago, IL) were studied in ten patients with cardiac arrhythmias. Multiple-serum disopyramide concentrations were obtained after a 300-mg oral dose. Each patient then received chronic oral therapy with the controlled-release preparation (400 to 1000 mg/day) on an every-12-hour schedule. At steady state, disopyramide trough concentrations were obtained. Serum disopyramide concentrations were determined by high performance liquid chromatography. The regimen was well tolerated by all patients. The mean (+/- SD) time to maximum concentration, maximum concentration, and concentrations 11 and 24 hours after the initial dose were 5.5 +/- 1.3 hours and 2.8 +/- 0.8, 2.0 +/- 0.9, and 1.2 +/- 0.5 micrograms/mL, respectively. A low Cmax to trough concentration ratio of 1.35 +/- 0.26 was observed after the initial dose. Linear regression analysis of the serum disopyramide concentrations 11 hours after initial dose (trough) versus trough concentrations at steady state (dose adjusted) showed a strong correlation (r = 0.87, intercept = 0.03, and slope = 1.9). Regression analysis also showed a strong relationship between the area under the curve (AUC) from time 0 to 11 hours after the initial dose and the trough at steady state (r = 0.86). CONCLUSIONS: The controlled-release preparation of disopyramide, when administered every 12 hours in patients with cardiac arrhythmias, should produce low peaks to trough fluctuations. Because disopyramide concentrations after the initial dose correlate well with trough concentrations at steady state, these concentrations may provide a simple and convenient method for prospective monitoring of disopyramide therapy in patients receiving the controlled-release preparation.

The influences of renal function and maturation on vancomycin elimination in newborns and infants.

The purpose of this study was to describe the maturation of vancomycin (V) clearance and the influence of altered renal function in infants on vancomycin using population pharmacokinetic methods. A population pharmacokinetic model was developed using NONMEM from clinical data obtained from 374 newborns and infants < 2 years of age (median age = 27 days) from four institutions. A total of 1103 serum V concentrations were used in the model development, including 311 with elevated serum creatinine (CR) (> 0.8 mg/dl) and more than 104 evaluations in infants older than 2 months of age. The final model was evaluated against a second data set of 160 concentrations from 67 infants at one of the institutions and then used to develop dosing guidelines. The data were best described by a two-compartment model. Weight and CR greatly influenced vancomycin elimination, while postnatal age and prematurity (< 28 weeks) were significant but less important predictors of V elimination. For the typical study infant (age = 27 days, CR = 0.6, WT= 1.8 kg, gestational age = 33.5 weeks), this results in VdSS = 0.79 l/kg and Cl = 0.066 l/h/kg. The validation data set showed the model to be unbiased. Dosing guidelines from this model, based on serum creatinine and gestational age at birth, performed better than published guidelines based on postconceptional age. Vancomycin clearance is initially reduced in premature infants and increases with postnatal age. Most of the age-related changes could be predicted by the concomitant fall in serum creatinine. Dosing guidelines that incorporate these factors are more likely to produce therapeutic V concentrations in infants.

Dichloroacetate: population pharmacokinetics with a pharmacodynamic sequential link model.

Dichloroacetate (DCA) is a small molecule that reduces ambient concentrations of lactate in man. It was the purpose of this study to develop pharmacokinetic and pharmacodynamic models for determination of a dose for a pivotal Phase III clinical trial of DCA in patients with traumatic brain injury (TBI). Population pharmacokinetic and pharmacodynamic models were developed for DCA using NONMEM software. The pharmacokinetic data were fit to a physiologic two-compartment model, and the pharmacodynamic data were fit to an indirect physiologic response model. Simulations were employed to evaluate various dosing strategies for consideration in a pivotal Phase III clinical trial of DCA. For the pharmacokinetic model, it was discovered that the clearance of DCA decreased on multiple dosing from 4.82 L/h to 1.07 L/h and that the pharmacokinetics and pharmacodynamics in TBI patients could not be predicted from normal volunteers. Population pharmacokinetic modeling and simulation of the expected effects of several dosing strategies were useful procedures for designing a Phase III trial.

Direct comparison of three methods for predicting digoxin concentrations.

Three methods of determining digoxin population pharmacokinetic parameters were compared for their abilities to predict 118 measured serum digoxin concentrations (SDCs) in 49 patients. NONMEM software (version IV) was used to generate a residual and a weighted residual for each measured-concentration-predicted-concentration pair. Prediction error analysis was done by a maximum likelihood technique that accounted for several within-patient measures. Data analysis also included graphic observation of weighted residuals (WRES) and calculation of the mean WRES and median absolute prediction error. A further parallel analysis was also carried out on subpopulations with and without concurrent quinidine and congestive heart failure (CHF). Method III was without bias in all subpopulations studied and had the smallest WRES in all populations. Method I was without bias in the overall population, however, it underpredicted SDCs in patients receiving quinidine and in those with CHF. Method II underpredicted SDCs in the overall population, those receiving quinidine, and in patients without CHF. There were no between-method differences in precision as assessed by absolute prediction error.

Pharmacokinetic considerations in the adolescent: non-cytochrome P450 metabolic pathways.

The non-oxidative metabolic reactions of methylation, acetylation, sulfation, glucuronidation, conjugation with amino acids (primarily with glycine), glutathione conjugation and esterase hydrolysis function to detoxify and enhance the elimination of drugs and pro-drugs, many of them as phase II reactions subsequent to oxidation. While the influence of maturation has been recognized in the development of hepatic oxidative capacity and specific pathways studied, considerably less attention has focused on the maturational effect in non-oxidative metabolism despite its role in drug deactivation, detoxification, and elimination. Consequently phase II metabolic capacities during adolescence remain primarily speculative. Conflicting data about one of these pathways, glucuronidation, suggest unexplored puberty- or gender-related phenomena influencing function in this system.

Intravitreal and plasma cidofovir concentrations after intravitreal and intravenous administration in AIDS patients with cytomegalovirus retinitis.

This study was undertaken to evaluate the intravitreal and plasma concentrations of cidofovir (HPMPC) after intravitreal and intravenous administration in AIDS patients with cytomegalovirus retinitis. Cohort series; undiluted vitreous and blood were collected from 9 patients at the time of pars plana vitrectomy. Vitreous samples from 9 eyes of 9 patients and plasma samples from 4 patients were assayed with high-performance liquid chromatography to determine cidofovir levels. The only eye that had a detectable vitreous concentration (673.7 ng/ml) was injected with 20 microg 24 hours prior to the surgery. The remaining samples including plasma were below the detection point of the assay (100 ng/ml) and were injected between 5 and 40 days prior to sampling. The intravitreal concentration of cidofovir in humans is consistent with pharmacokinetics data in laboratory animals, and suggests that the long duration of antiviral effect (1-3 months) in clinical trials is due to a prolonged intracellular half-life in retinal tissue.

Use of opportunistic clinical data and a population pharmacokinetic model to support dosing of clindamycin for premature infants to adolescents.

Clindamycin is commonly prescribed to treat children with skin and skin-structure infections (including those caused by community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA)), yet little is known about its pharmacokinetics (PK) across pediatric age groups. A population PK analysis was performed in NONMEM using samples collected in an opportunistic study from children receiving i.v. clindamycin per standard of care. The final model was used to optimize pediatric dosing to match adult exposure proven effective against CA-MRSA. A total of 194 plasma PK samples collected from 125 children were included in the analysis. A one-compartment model described the data well. The final model included body weight and a sigmoidal maturation relationship between postmenstrual age (PMA) and clearance (CL): CL (l/h) = 13.7 × (weight/70)(0.75) × (PMA(3.1)/(43.6(3.1) + PMA(3.1))); V (l) = 61.8 × (weight/70). Maturation reached 50% of adult CL values at ~44 weeks PMA. Our findings support age-based dosing.

Assessment of lopinavir pharmacokinetics with respect to developmental changes in infants and the impact on weight band-based dosing.

Improved antiretroviral therapies are needed for the treatment of HIV-infected infants, given the rapid progression of the disease and drug resistance resulting from perinatal exposure to antiretrovirals. We examined longitudinal pharmacokinetics (PK) data from a clinical trial of lopinavir/ritonavir (LPV/r) in HIV-infected infants in whom therapy was initiated at less than 6 months of age. A population PK analysis was performed using NONMEM to characterize changes in lopinavir (LPV) PK relating to maturational changes in infants, and to assess dosing requirements in this population. We also investigated the relationship between LPV PK and viral dynamic response. Age and ritonavir concentrations were the only covariates found to be significant. Population PK of LPV was characterized by high apparent clearance (CL/F) in young infants, which decreased with increasing age. Although younger infants had lower LPV concentrations, the viral dynamics did not correlate with initial LPV exposure. Monte Carlo simulations demonstrated that WHO weight band-based dosing recommendations predicted therapeutic LPV concentrations and provided drug exposure levels comparable to those resulting from US Food and Drug Administration (FDA)-suggested dosing regimens.