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There is an urgent need to identify safe and effective combination treatments for multidrug-resistant (MDR) Mycobacterium tuberculosis infection (TB). Bedaquiline, a new diarylquinoline, is approved for the treatment of MDR pulmonary TB in combination with other drugs, which could include rifabutin, which is also used to treat drug-resistant TB. Both rifabutin and bedaquiline are metabolized via cytochrome P450 3A4, and rifabutin is an inducer of this enzyme. Bedaquiline is metabolized into its primary N-monodesmethyl metabolite, M2, and further desmethylated into an N-didesmethyl metabolite, M3. Both metabolites are cytotoxic and induce phospholipidosis. The effect of rifabutin on the generation and disposition of the 2 metabolites was investigated in healthy adult volunteers coadministered bedaquiline and either rifabutin or rifampin. Subjects received single oral doses (400 mg) of bedaquiline on days 1 and 29. Oral rifabutin (300 mg) or rifampin (600 mg) were given daily on days 20-41. In the rifabutin group maximum M2 concentrations (Cmax ) increased significantly (P < .001) from 47.59 to 79.53 ng/mL, and clearance slowed slightly (P = .01). This resulted in significantly (P < .001) increased overall exposure (area under the concentration-time curve [AUC0-τ ]). Peak concentrations of M3 increased approximately 3-fold with little decline thereafter. In rifampin recipients M2 Cmax doubled (48.44 to 101.52 ng/mL), but M2 clearance and time to Cmax significantly (P < .001) increased, and AUC0-∞ and mean residence time significantly decreased (P < .001). Peak M3 concentrations increased 4-fold and rapidly declined. Although both rifamycins accelerate desmethylation of bedaquiline and M2, differences in clearance resulted in sustained elevations of both metabolites during rifabutin, but not rifampin, treatment.

The effectiveness and safety of valsartan have not been assessed in hypertensive children. Therefore, hypertensive patients aged 6 to 16 years (n=261) were randomized to receive weight-stratified low- (10/20 mg), medium- (40/80 mg), or high-dose (80/160 mg) valsartan for 2 weeks. After 2 weeks, patients were randomized to a 2-week placebo-controlled withdrawal phase. Dose-dependent reductions in sitting systolic blood pressure (SSBP) and sitting diastolic blood pressure (SDBP) were observed after 2 weeks (low dose, -7.9/-4.6 mm Hg; medium dose, -9.6/-5.8 mm Hg; high dose, -11.5/-7.4 mm Hg [P

An open-label, single-dose study is conducted in 26 children with hypertension to characterize the pharmacokinetics of valsartan. Valsartan is administered as an oral suspension (dose of 2 mg/kg), with the maximum single dose being 80 mg. Subjects are stratified into 4 age categories: group 1, 1 to less than 4 years; group 2, 4 to less than 6 years; group 3, 6 to less than 12 years; group 4, 12 to 16 years. Blood samples are collected before and for 24 hours after dosing to quantitate valsartan. Because the body weight of most children in groups 3 and 4 exceeds 40 kg and they received a dose of less than 2 mg/kg, major pharmacokinetic parameters are dose normalized for comparison across the age groups. Dose-normalized maximum plasma concentration and area under the plasma-concentration curve and body weight-normalized apparent oral clearance are comparable for the 4 groups (P > or = .1011). Body weight-normalized apparent oral clearance ranges from 0.061 to 0.089 L/h/kg.

Background Cancer patients undergoing chemotherapy often develop anemia, which can increase the risk for transfusions and fatigue. The recombinant erythropoiesis-stimulating agent darbepoetin alfa can effectively treat chemotherapy-induced anemia (CIA) in adults, but limited data are available regarding its use in pediatric cancer patients. The goals of this phase 1, open-label, uncontrolled study were to assess the pharmacokinetic profile and safety of darbepoetin alfa in pediatric patients with CIA. Procedure Pediatric patients with nonmyeloid malignancies and CIA received up to six doses of darbepoetin alfa 2.25 mcg/kg subcutaneously. After the first dose, the pharmacokinetic properties of darbepoetin alfa were assessed during a 14-day sampling period. All subsequent doses were given weekly with predose blood samples collected before study drug administration. Results After a single dose of darbepoetin alfa, the mean (SD) peak serum concentration was 10.5 (3) ng/ml, and the median time to peak concentration was 71.4 hr. Darbepoetin alfa exhibited a mean (SD) terminal half-life of 49.4 (32) hr. Upon repeated weekly administration, no evidence of darbepoetin alfa accumulation was observed though there was high intra- and inter-individual variability. In addition, darbepoetin alfa was well tolerated; some study patients experienced increases in hemoglobin. Conclusions The pharmacokinetic profile of darbepoetin alfa indicated that it was slowly absorbed and exhibited a long terminal half-life in these pediatric study patients with CIA. Pediatr Blood Cancer 2007;49:687–693. © 2006 Wiley-Liss, Inc.

Quinapril pharmacokinetics were studied in infants and children using a novel study design that allowed substitution of quinapril for one dose of the current chronic angiotensin-converting enzyme (ACE) inhibitor treatment. A total of 24 patients ranging in age from 2.5 to 82 months who were receiving an ACE inhibitor held their usual treatment on the study day and received a 0.2-mg/kg dose of quinapril syrup. Blood samples were collected through 24 hours postdose, and plasma was analyzed for quinapril and its active metabolite, quinaprilat. Quinapril was rapidly converted to quinaprilat. Quinaprilat concentrations generally peaked 1 to 2 hours postdose and declined with a mean half-life of 2.30 hours. Dosing on a mg/kg basis resulted in quinaprilat AUC and Cmax values that were generally comparable across the age range of patients in this study. The overall mean AUC0-infinity was 993 ng.h/mL (range: 533-1523), and mean Cmax was 260 ng/mL (range: 70.0-445.5). Quinaprilat CL/F correlated well with body size (body surface area or weight) and creatinine clearance (mL/min). Pharmacokinetic results after a 0.2-mg/kg dose in infants and children are comparable to those observed following a 10-mg dose in adults.

The pharmacokinetics of intravenous famotidine (0.5 mg/kg, maximum 20 mg) were evaluated in 18 pediatric patients (ages 1-18 years) with stable, chronic renal insufficiency. Subjects were stratified by calculated creatinine clearance (Clcr) into mild (Clcror = 50 to90 mL/min/1.73 m2), moderate (Clcror = 25 to50 mL/min/1.73 m2), and severe (Clcror = 10 mL/min/1.73 m2) renal insufficiency groups. Significant differences between the mild, moderate, and severe groups were found for elimination rate (Kel), apparent elimination half-life (t1/2), area under the curve (AUC), and total plasma clearance (Clp) (p0.01). Famotidine renal clearance (Clr) was found to be significantly different between the mild and severe groups (p0.05). A linear relationship was observed between Clcr and Clp (p0.0001; R2 = 0.70). No significant differences in nonrenal clearance (Clnr) were found between groups; however, Clnr as a percentage of Clp was significantly different in the severe group (92.9% +/- 7.3% Clnr) compared to the combined mild and moderate groups (21.9% +/- 45.6% Clnr) (p0.05). It was concluded that the pharmacokinetics of famotidine are significantly altered in children with chronic renal insufficiency; accordingly, dosing should be based on glomerular filtration rate (i.e., Clcr).

In this study, the authors evaluate the pharmacodynamics, safety, and acceptability of a new cherry-flavored oral syrup formulation of midazolam. This randomized, double-blind, parallel-group, dose-ranging clinical trial of oral midazolam was conducted at seven U.S. health care institutions focused on pediatric clinical pharmacology research (i.e., the PPRU Network). Pediatric patients (n = 85, ages 6 months through 15 years) underwent invasive procedures and were randomized to a single oral dose of midazolam syrup (0.25, 0.5, or 1.0 mg/kg). Patient taste acceptability of midazolam syrup was evaluated at the time of oral administration. Pharmacodynamic measurements included (1) sedation score using a 5-point scale at baseline and 10-, 20-, and 30-minute postdose intervals and (2) anxiety score using a 4-point scale at the time of separation from caretakers and, when applicable, at the time of mask anesthetic induction. Midazolam and alpha-hydroxymidazolam plasma concentrations were measured at all pharmacodynamic measurement time points. Adverse events were monitored continuously during the study. Most patients (99%) accepted the syrup without difficulty. Satisfactory sedation was achieved within 30 minutes by 81% of patients. The anxiety score at the time of caretaker separation and mask anesthetic induction was satisfactory for 87% and 91% of patients, respectively. A significant linear relationship between plasma drug concentration and maximal sedation score, but not anxiety score, was observed. The occurrence of adverse events was consistent with the known safety profile of midazolam. The most commonly reported adverse events were hiccoughing, hypoxemia, nausea, and emesis. It was concluded that a new oral syrup formulation of midazolam, 0.25 to 1.0 mg/kg, effectively induced rapid-onset, dose-related, adequate, and safe sedation and anxiolysis in pediatric patients who underwent operative procedures. Sedative effects were related to plasma concentrations of both midazolam and the primary metabolite, alpha-hydroxymidazolam. Oral midazolam, 1.0 mg/kg, administered within 30 minutes of the expected procedure or anesthetic induction should provide safe and effective sedation to a majority of children ages 6 months to 16 years.

Objective criteria for ending mechanical ventilation have not been established for infants and children. A recent study in adult patients developed two new indexes, the Rapid Shallow Breathing Index (RSB) and the CROP Index for predicting success or failure of extubation. We decided to evaluate the applicability of these indices to intubated, mechanically ventilated pediatric patients. For this evaluation the indices were adapted to the physiology of infants and children. A pneumotachograph was used to measure spontaneous tidal volume, respiratory rate and dynamic compliance. The tidal volume and the dynamic compliance were corrected for the patient's body weight. Based on the data collected a cutoff value for each index was determined. Of 47 sets of patient data, 38 (81%) were collected during successful extubations, 9 (19%) during failed extubations. A modified CROP index value of > or = 0.1 ml x mmHg/bpm/kg and a modified RSB index value of or = 0.1 and < or = 11 for the modified CROP index and RSB index, respectively, appear to be predictive of successful extubation in the pediatric population. Our data identifies the modified CROP index as a superior discriminator between successful and unsuccessful extubation.

The pharmacokinetic characteristics of ticarcillin and clavulanic acid were determined after the first dose (n = 22) and again under steady-state conditions (n = 16) in a group of infants and children. Study subjects ranged in age from 1 month to 9.3 years; all but 3 study patients were 6 months of age or older. Each patient received 50 mg of ticarcillin and 1.7 mg of clavulanic acid (30:1 ratio) per kg of body weight given intravenously every 4 hours. Elimination half-life, steady-state volume of distribution, and body clearance averaged 1.1 hours, 0.22 L/kg, and 2.7 mL/min/kg, respectively, for ticarcillin, and 0.9 hours, 0.4 L/kg, and 6.2 mL/min/kg, respectively, for clavulanic acid. A total of 71% of the ticarcillin and 50% of the clavulanic acid dose were excreted unchanged in the urine over the 4-hour sampling period. Corresponding renal clearances averaged 2.1 and 3.2 mL/min/kg for ticarcillin and clavulanic acid, respectively. No differences were observed between first dose and steady-state evaluations in the pharmacokinetic behavior of either agent. In contrast, the pharmacokinetic behavior of clavulanic acid was significantly different from that observed for ticarcillin. These pharmacokinetic data combined with known in vitro susceptibilities of important clinical pathogens support a dose of 80 mg of ticarcillin and 2.7 mg/kg clavulanic acid per kg body weight given as a fixed dose combination every 8 hours for the treatment of most systemic infections that occur outside the central nervous system.

The efficacy and pharmacokinetics of piperacillin monotherapy were studied in 46 patients with cystic fibrosis. Two patients were dropped from the study within 24 hr of enrollment because of drug-associated nausea and vomiting. Initially fourteen older patients (> 12 years) receiving piperacillin 450 mg/kg/day underwent a preliminary evaluation. Based on the results, 30 younger patients (⩽ 12 years) randomized in a double-blind fashion received either 600 or 900 mg/kg/day of piperacillin in six divided doses. Pharmacokinetic parameter estimates for t1/2, Vdss, and Cl were similar for first dose and steady-state evaluations. In 27 patients, approximately 43% of the administered dose was recovered in the urine after 4 hr. Piperacillin CiR averaged 49% of the total Cl. No difference in overall clinical efficacy could be identified between 600 and 900 mg/kg/day of piperacillin using two different objective scoring systems. Although a reduction in sputum Pseudomonas colony counts was greater following the 900 mg/kg/day regimen, this appeared to be independent of clinical effect. In 14 patients (32%), a distinct adverse serum-sicknesslike reaction was observed. The incidence of this reaction appeared to increase as the dose of piperacillin increased. All signs and symptoms of this reaction resolved within 36 hr of discontinuing piperacillin administration but recurred immediately on rechallenge in four patients. All patients with the adverse reaction were subsequently treated with β-lactam antibodies without ill effect. Overall, clinical improvement appeared to be independent of the piperacillin dose. Our data support the use of total daily piperacillin dosages not exceeding 600 mg/kg. Pediatr Pulmonol 1987; 3:101–109.

Nine children underwent ten bone marrow transplants for malignancies and were supported by parenteral alimentation administered in cyclic fashion 18 hours daily. Children received cyclic parenteral nutrition for an average of 29 days, which provided a caloric intake (mean +/- SD) of 55.9 +/- 18.1 Kcal/kg/day, and a nitrogen intake of 0.28 +/- 0.08 g/kg/day. Nutritional status was assessed using nitrogen balance, creatinine-height index, and visceral protein concentrations including serum albumin, transferrin, and prealbumin. Minimal transient elevation in tests of liver function were observed without marked derangement in blood glucose, electrolytes, or osmolality. Unlike prealbumin, determinations of nitrogen balance, creatinine-height index, serum albumin and transferrin concentrations did not parallel changes in clinical status. Cyclic parenteral alimentation is a practical approach to the maintenance of nutrition during intensive antitumor therapy and provides an infusion-free period for the administration of drugs and blood transfusions without interfering with nutritional support. Prealbumin accurately reflects changes in the patient's clinical status at any point and is easily and reliably determined.

The single-dose pharmacokinetics of aztreonam was evaluated in 10 clinically stable subjects with cystic fibrosis. Each child received 30 mg aztreonam/kg intravenously over 2 to 3 minutes. Multiple timed blood samples were obtained over 8 hours for determination of aztreonam elimination kinetics; all urine excreted for 24 hours was collected in timed aliquots for the determination of aztreonam and its microbiologically inactive metabolite, SQ 26,992. Aztreonam pharmacokinetic parameters were determined by model-independent methods. Mean t1/2, steady-state volume distribution, and body clearance were 1.3 hr, 0.25 L/kg, and 127.2 ml/min/1.73m2, respectively. In 9 of the 10 subjects, two-compartment pharmacokinetic analysis was possible and compared favorably with model-independent parameter estimates. Twenty-four-hour urinary recovery of aztreonam was 76.3% of the administered dose; 2.6% was recovered as the metabolite SQ 26,992. The renal clearance of aztreonam averaged 92.5 ml/min/1.73m2. When these data are combined with in vitro susceptibility data for aztreonam against Pseudomonas aeruginosa isolated from the sputum of patients with cystic fibrosis, a dose of 200 mg aztreonam/kg/day divided six hourly would be predicted to maintain serum concentrations above the minimum inhibitory concentration (MIC) for these organisms for the majority of the dosing interval.

Seventeen patients with cystic fibrosis (CF) and pulmonary exacerbations were randomly assigned to two treatment groups: piperacillin 600 mg/kg/day (P), and piperacillin 600 mg/kg/day plus tobramycin (PT), in order to determine the safety and pharmacokinetics of high-dose piperacillin and whether piperacillin alone was effective for the treatment of Pseudomonas infections. The mean half-life of piperacillin was 0.54 hours, with a peak concentration of 232 micrograms/ml. No differences between P and PT groups were noted in clinical assessment, as judged by Shwachman scores, pulmonary function testing, or weight gain. However, during the course of treatment, quantitative sputum cultures decreased by greater than 10(2) colony-forming units in only 5 out of 19 Pseudomonas isolates from the P group, compared with 12 of 19 isolates from the PT group (P less than 0.03, Chi-square). Although emergence of resistance was not seen, one isolate had an increase in minimum inhibitory concentration from 8 to 128 micrograms/ml. There were no serious adverse reactions to piperacillin; only one patient developed fever possibly related to piperacillin. Therapy with high-dose piperacillin was safe in children with CF. Treatment with piperacillin alone was less effective than combination therapy with gentamicin for reduction in titer of Pseudomonas in sputum. However, the role of antimicrobial agents in the treatment of CF remains undefined. A double-blind placebo-controlled trial is indicated.