Considerations in the rational design and conduct of phase I/II pediatric clinical trials: avoiding the problems and pitfalls.

Over the past decade, there has been a heightened awareness of the need to include children in the drug development process. With this awareness has come an expansion of the infrastructure for conducting studies in children and an increase in the sponsorship of pediatric clinical trials. However, the growth in pediatric research has, in many cases, not been accompanied by an increase in the involvement of trained pediatric investigators when it comes to trial design and/or interpretation. Pediatric phase I/II protocols continue to span a spectrum from those that are carefully constructed to those that are poorly designed. This paper highlights the basic elements of phase I/II protocols that merit unique consideration when the clinical trial involves children. Illustrations are provided from our experience, which highlight problems that may arise when trials are not designed with the pediatric patient in mind.

Nifedipine poisoning in a child.

A 14-month-old child ingested approximately 800 mg (70 mg/kg) of nifedipine. When first examined, the child was unresponsive, markedly hypotensive, and hyperglycemic. According to electrocardiographic results, there was a third-degree atrioventricular block that rapidly progressed to cardiac arrest. Following successful cardiopulmonary resuscitation, mechanical ventilation and resuscitation with intravenous normal saline, calcium chloride and dopamine were required to restore perfusion, reverse metabolic acidosis, and stabilize vital signs. Complications related to nifedipine intoxication included the development of pulmonary edema and possible infarction in the posterior parietal and occipital lobes associated with cortical blindness and the development of seizures with an abnormal electroencephalogram. The patient recovered without clinically apparent residua. Massive nifedipine overdose in infants represents a potentially life-threatening event that requires prompt medical attention. Reported cases of nifedipine intoxication were reviewed and therapeutic interventions were discussed.

Cefpodoxime pharmacokinetics in children: effect of food.

BACKGROUND: Cefpodoxime, an oral third generation cephalosporin antibiotic, is used for the treatment of acute upper respiratory tract infection caused by susceptible bacteria in children 5 months to 12 years of age. We report the results of a randomized two-way crossover study designed to characterize the disposition of a single dose (10 mg/kg) of cefpodoxime proxetil oral suspension in children, under fed and fasted conditions. METHODS: Seventeen children (8.4 months to 12.2 years old, seven female) participated in this study. Each subject received a single 10-mg/kg dose of cefpodoxime proxetil oral suspension, after a predose fast and again coadministered with food. Repeated blood samples (n=10) were obtained during 12 h postdose and cefpodoxime was quantified from plasma by high performance liquid chromatography. Plasma concentration vs. time data were curve fit for each subject with a nonlinear weighted least squares algorithm, and pharmacokinetic parameters were determined from the polyexponential estimates. RESULTS: Cefpodoxime disposition was best characterized using a one-compartment open model with first order absorption. The area under the plasma concentration vs. time curve, Cmax and Ke were not significantly different between fed and fasted conditions. However, Tmax was significantly prolonged (fed=2.79+/-1.10 h vs. fasted=1.93+/-0.54 h) and Ka was significantly smaller (fed=0.42+/-0.14 h(-1) vs. fasted=0.81+/-0.72 h(-1)) in the fed state. CONCLUSIONS: Administration of cefpodoxime in the presence of food affected the rate but not the extent of absorption. Cefpodoxime proxetil oral suspension can be administered without regard to meals in children 6 months to 12 years of age.

Pharmacokinetics of high dose thiotepa in children undergoing autologous bone marrow transplantation.

Pharmacokinetics of high dose thiotepa was studied in 10 children who received this drug as a 2 h infusion at a dose of 300 mg/m2 daily for 3 days. The thiotepa was quantitated using a modification of a previously published gas chromatographic method. Samples were obtained at predetermined times post infusion. The peak plasma concentrations immediately following the infusion ranged from 5.5 to 25.2 (2.0 +/- 6.6) mg/l and the 8 h post infusion ranged from 0.06 to 0.7 (0.32 +/- 0.21) mg/l. The disposition of thiotepa was best described as a simple one compartment open model. The mean (+/- SEM) values for apparent elimination half-life (t1/2 beta), total plasma clearance (CL) and steady volume of distribution (VDss) were 1.3 x h, 11.25 (1.73) l/h/m2 and 19.38 (2.58) l/m2 respectively. In conclusion the pharmacokinetics of high dose thiotepa in children between 2 and 12 years of age do not appear to vary from those reported in children receiving 75 mg/m2 or adults receiving similar doses.

Influence of diurnal blood pressure variations on target organ abnormalities in adolescents with mild essential hypertension.

As hypertensive target-organ damage has been associated with diminished diurnal blood pressure (BP) variation in adults, we compared diurnal BP patterns of hypertensive adolescents with left ventricular hypertrophy with normotensive and hypertensive adolescents with normal left ventricular mass. In addition, the frequency of microalbuminuria (Malb), hyperfiltration, and reduced renal functional reserve (RFR) was evaluated in adolescents with normal BP and untreated borderline and mild essential hypertension. Thirty-three normotensive (NT) adolescents, 14.5+/-2.1 years (mean +/- SD), and 29 untreated borderline and mildly hypertensive (HT) adolescents, 14.6+/-2.4 years, wore the SpaceLabs 90207 ambulatory BP monitor for 24 h. Left ventricular mass was measured by M-mode echocardiography and then indexed (LVMI) to the cube of height. Creatinine clearance (Clcr) and urine Malb was measured on 24 h collection and RFR by change in creatinine clearance after an oral protein load. Diurnal BP change was expressed as the absolute and percent day-night BP fall and cusum derived plot height (CPH) and circadian alteration magnitude (CDCAM). Groups were compared using analysis of covariance with adjustments for race, gender, and body mass index. All NT and 19 HT subjects (HT-1) had normal LVMI at 22.2+/-5.3 and 25.8+/-3.8 g/m3, respectively. Ten HT (HT-2) had increased LVMI of 36.9+/-5.2 g/m3. No significant difference was found for absolute or percent day-night BP fall or CDCAM between groups. Nocturnal systolic BP was correlated most closely with LVMI (r = 0.41, p = .001). Clcr, Malb, and RFR did not differ between the groups. In conclusion, adolescents with borderline and mild essential hypertension and left ventricular hypertrophy have similar levels of diurnal BP fall, urine Malb excretion, and RFR compared to normotensive and hypertensive adolescents with normal left ventricular mass.

Pharmacokinetics and pharmacodynamics of bumetanide in critically ill pediatric patients.

This prospective, open-label, clinical trial was conducted to describe the pharmacology of bumetanide in pediatric patients with edema. Nine infants, children, and young adults with edema who were selected for diuretic therapy were studied. After a brief baseline period, each patient received parenteral bumetanide 0.2 mg/kg divided into two equal doses and administered every 12 hours. Urine excretion rate, fractional and total excretion of Na+, Cl-, and K+, creatinine clearance, and plasma and urine concentrations of bumetanide were measured at multiple intervals after drug administration. Bumetanide caused significant increases in the excretion rate of urine and each measured electrolyte. Unexpectedly, creatinine clearance increased dramatically after each dose. Adverse effects, including hypokalemia and hypochloremic metabolic alkalosis, were evident by the end of the treatment period. The plasma pharmacokinetics of bumetanide revealed mean +/- standard deviation values for total clearance and apparent volume of distribution of 3.9 +/- 2.4 mL/min/kg and 0.74 +/- 0.54 L/kg, respectively. Patients excreted an average of 34% of each dose unchanged in the urine over 12 hours. Plasma concentrations of bumetanide accurately predicted several renal effects using a link model with similar pharmacodynamic parameters in each case. Parenteral bumetanide 0.1 mg/kg administered every 12 hours produced significant beneficial and adverse effects in these critically ill pediatric patients with edema. Pharmacokinetic parameters are similar to those previously reported for infants. Plasma concentrations of bumetanide can predict effect-compartment pharmacodynamics.

Age-related differences in digoxin toxicity and its treatment.

Digoxin toxicity remains a common medical problem for both adults and children. In addition to a vastly improved understanding of the mechanisms for digoxin action on the heart, there are now data which clearly demonstrate that there are potentially important developmental differences in both the pharmacodynamics and pharmacokinetics of digoxin which have a direct impact on its efficacy and toxicity profile. The developmental pharmacokinetics of the drug have been extensively studied such that profiles for age-dependent differences in the apparent volume of distribution, plasma and renal clearance and elimination half-life now exist. It is these data which have also produced the current age-specific dosing guidelines for the therapeutic administration of digoxin in various paediatric subpopulations. Despite this new knowledge, both accidental and iatrogenic digoxin toxicity still occurs in paediatric patients, with potentially life-threatening arrhythmias being produced when steady-state serum digoxin concentrations exceed 5.1 nmol/L. Consequently, the clinician may be faced with the decision to use antidotal therapy with digoxin-specific Fab fragments (d-Fab). This article reviews the developmental basis for digoxin disposition and its pharmacological and toxic effects. Additionally, the treatment of acute digoxin toxicity in children is reviewed, especially as pertains to the therapeutic use of d-Fab.

Comparison of the pharmacokinetics of naproxen tablets and suspension in children.

Twenty-three children, aged 8 to 14 years, with postoperative pain, were randomly assigned to receive a fixed 250-mg dose (4.66-7.58 mg/kg) of naproxen as either a liquid suspension or tablet. After an overnight fast, the serum concentrations were measured before and at 0.5, 1, 2, 3, 4, 8, 12, 18, and 24 hours after administration of naproxen. The concentration versus time data were best fit to a one-compartment open model. The area under the concentration versus time curve, apparent volume of distribution (VDss/F), and elimination parameters (CL/F, Ke, elimination half-life) were similar in children who received suspension or tablets. Although the apparent maximum peak plasma concentration (Cmax) was greater in children who received tablets compared with those who received the suspension, Cmax/area under the curve (AUC), apparent time to maximum peak concentration (tmax), Ka, and estimated time to 10%, 50%, and 90% absorption (T10, T50, T90) were not different. The dose range was relatively narrow; hence, direct relationships between dose and elimination parameters, VDss/F, apparent tmax, Ka, T10, T50 or T90 were not observed. Neither VDss/F or CL/F were age related over the relatively narrow range of ages that were studied. Elimination of naproxen in our patients was more rapid than has previously been reported in children or adults, however. From a practical standpoint, naproxen tablets and suspension seem to be bioequivalent in fasting children ages 8 to 14 years.

Pharmacokinetics and pharmacodynamics of ranitidine in neonates treated with extracorporeal membrane oxygenation.

The pharmacokinetics and pharmacodynamics of ranitidine were studied in 13 term neonates with stable renal and hepatic function who were treated with extracorporeal membrane oxygenation (ECMO). Ranitidine was initially administered as a single 2 mg/kg dose over 10 minutes and intragastric pH was monitored to determine response. Within 90 minutes after administration of ranitidine, intragastric pH for all of the patients whose initial reading was < or = 4 had increased to > 5. Intragastric pH remained > 4 for a minimum of 15 hours. Mean +/- 1 standard deviation elimination half-life was 6.61 +/- 2.75 hours, and 41.5 +/- 22.2% of the single dose was eliminated in urine within 24 hours. Total plasma clearance of ranitidine correlated well with estimated glomerular filtration rate. Twenty-four hours after the initial dose, a continuous infusion of ranitidine (2 mg/kg/24 hr) was started and continued for 72 hours or until ECMO was discontinued. Eleven patients completed 48 hours of continuous infusion and seven completed all 72 hours. Plasma clearance and elimination half-life were determined from steady-state plasma ranitidine concentrations 24, 48, and 72 hours after the start of the infusion. There were no significant differences in clearance between these intervals. These data suggest that for term neonates with stable renal and hepatic function, ranitidine does not need to be administered more frequently than every 12 hours. A continuous infusion of 2 mg/kg/24 hours maintained intragastric pH above 4 in more than 90% of our patients, and in our opinion is the preferred method for delivering ranitidine to term neonates undergoing ECMO who require H2 antagonists. Response to therapy should be monitored by repeated measurement of gastric pH and the dose should be adjusted accordingly.

Pharmacokinetics and pharmacodynamics of famotidine in children.

The pharmacokinetics and pharmacodynamics of intravenous famotidine were studied in 12 children (1.1-12.9 years of age; mean weight +/- standard deviation = 27.6 +/- 21.2 kg) who were given the drug for prophylactic management of stress ulceration. After a 0.5-mg/kg infusion of famotidine, timed blood (n = 10) and urine (n = 6) samples and repeated evaluations of intragastric pH (n = 13) were obtained from each subject. Pharmacokinetic parameters were determined from curve fitting of serum concentration data. The mean (+/- SD) maximum serum concentration (Cmax) was 527.6 +/- 281.2 ng/mL, the elimination half-life (t1/2) was 3.2 +/- 3.0 hours, and the apparent steady-state volume of distribution (Vdss) was 2.4 +/- 1.7 L/kg. Plasma clearance (Cl) and renal clearance (ClR) were 0.70 +/- 0.34 L/hr/kg and 0.43 +/- 0.24 L/hr/kg, respectively. Over 24 hours, 73.0 +/- 27.3% of the dose was excreted unchanged in the urine (Fel). Pharmacodynamic analysis of gastric pH data using the sigmoid Emax model predicted that 50% of the maximal effect of famotidine (EC50) occurs at a serum concentration of 26.0 +/- 13.2 ng/mL. Children who did not have an initial intragastric pH < or = 4 did not have a significant response in pH after receiving famotidine. Although Vdss and Cl were higher in these children than those seen in adults, statistically significant relationships between these parameters and age were not observed in the study population. The pharmacodynamics and pharmacokinetics of famotidine in children older than one year of age appear to be similar to those noted in adults.

The pharmacokinetics of irbesartan in hypertensive children and adolescents.

An open-label study was conducted to characterize the pharmacokinetics and antihypertensive response to irbesartan in children (1-12 years) and adolescents (13-16 years) with hypertension. Patients received single once-daily oral doses of irbesartan 2 mg/kg (maximum of 150 mg once daily) for 2 to 4 weeks (+/- nifedipine or hydrochlorothiazide). Plasma irbesartan concentrations were determined by a validated high-performance liquid chromatography/fluorescence method from blood samples taken predose, up to 24 hours after dosing on Day 1, and up to 48 hours after the final dose. The plasma concentration-time profiles were similar between the 6- to 12-year and the 13- to 16-year age groups and to that previously determined from a study of adult subjects receiving approximately 2 mg/kg (i.e., 150 mg) oral irbesartan once daily. Mean reductions in systolic/diastolic blood pressure were 16/10 mmHg at Day 28 with irbesartan monotherapy (n = 8). Irbesartan was well tolerated and may be a treatment option for pediatric hypertensive patients.

Diurnal blood pressure patterns in normotensive and hypertensive children and adolescents.

As abnormalities in diurnal ambulatory blood pressure (BP) have been associated with hypertensive target organ damage in adults, we investigated the diurnal systolic BP (SBP) and diastolic BP (DBP) patterns of 54 normotensive children, age 13.4 +/- 3.0 years, and 45 untreated borderline and mildly hypertensive children, age 14.4 +/- 2.6 years. Subjects wore the SpaceLabs 90207 ambulatory BP monitor for 24 h. BP was measured q 15 min from 08.00-21.00 h then q 30 min from 21.00-08.00 h. Nocturnal BP fall, the night-day ratio and cusum derived measures were calculated from time-weighted daytime and night-time SBP and DBP. The groups were compared using analysis of covariance with adjustment for age, race, gender and body mass index. The influence of age, gender and race on the diurnal BP profile was also examined. Nocturnal SBP fall was greater in hypertensive compared to normotensive subjects (17.1 +/- 6.7 vs 14.6 +/- 7.1 mm Hg; unadjusted mean +/- s.d., P = 0.022). Normotensive and hypertensive groups did not differ in nocturnal DBP fall or SBP or DBP night-day ratio. Race appeared to influence the diurnal BP pattern as black subjects had less nocturnal SBP fall (12.9 +/- 6.9 vs 17.1 +/- 6.5 mm Hg; P < 0.005) and a higher night-day SBP ratio (90.1 +/- 5.3 vs 86.7 +/- 4.6%; P < 0.005) than white subjects. In conclusion, hypertensive children and adolescents have a similar diurnal BP pattern as their normotensive counterparts, except that the entire BP profile is shifted upward with a greater absolute fall in SBP at night. Race also appears to influence the diurnal BP profile of normotensive and hypertensive children and adolescents.

Evaluation of home blood pressure monitors in children and adolescents.

OBJECTIVE: This study was designed to adapt commercially available home blood pressure monitors for use in children ages 4 to 18 years and to compare the recordings obtained from the adapted devices to those obtained using a standard mercury sphygmomanometer. METHODS: Sequential same-arm blood pressures were measured by trained observers in 106 children, ages 4 to 18 years, using a calibrated mercury-gravity manometer (reference device) as the standard method, and 3 test devices (an aneroid manometer and two semiautomated oscillometric devices). For each patient, mid-arm circumference was measured and appropriate blood pressure cuff size was selected. Systolic and diastolic pressures were measured by trained observers using the reference device and the aneroid manometer in accordance with criteria established by the Second Task Force on Blood Pressure Control in Children. Other than variation in cuff size, all manufacturers' recommendations were followed for each test device. RESULTS: Outcome was assessed using criteria established by the British Hypertension Society (BHS) and the Association for the Advancement of Medical Instrumentation (AAMI). The aneroid manometer consistently received a grade of A using BHS criteria and also passed using AAMI criteria. Neither of the two semiautomated monitors achieved a passing grade, although the Labtron monitor performed slightly better than the Marshall 85 monitor. CONCLUSIONS: Home blood pressure monitors must be validated for use in children prior to widespread use. Given appropriate training and verification of observer accuracy, the aneroid manometer can be recommended for home use in children ages 4 to 18 years.

The pharmacology and therapeutics of diuretics in the pediatric patient.

Selection of appropriate diuretic therapy in children is hampered by a lack of age-specific pharmacokinetic and pharmacodynamic data, especially in premature neonates. Well-designed clinical trials in neonates, infants, and younger children are necessary prerequisites to safer and more efficacious diuretic therapy.

Trials of antihypertensive therapies in children.

Clinical trials assessing the safety, effectiveness and pharmacokinetics of new antihypertensive medications have been numerous as new classes of medications have been developed and brought to market over the past two decades. However, very few clinical trials have been initiated and completed in children with hypertension. Excluding diuretics, only one antihypertensive medication marketed within the past 20 years has any pediatric pharmacokinetic or dosing information published in the drug label and none have a pediatric indication. There are many reasons that these studies have not been done. Summation of the data collected in large epidemiologic studies that establish normal blood pressure and define hypertension using casual measurements have been a relatively recent event in pediatrics. Although ambulatory blood pressure measurement has been studied for the past decade there is still uncertainty with respect to the standardization of devices, measurement technique and normal values in a multi-racial pediatric population. As a result, no large scale, industry-sponsored clinical trials involving antihypertensive therapy have employed this measurement technique in children. In recognition of this problem, US Congress passed the Food and Drug Administration Modernization Act in 1997. Among the many provisions of this law, the US Food and Drug Administration (FDA) is required to publish a list of approved drugs for which additional information may prove beneficial for children. This law and subsequent action by the FDA also provides a mechanism by which manufacturers may gain six months of additional market exclusivity if adequate and well-controlled pediatric trials are completed and submitted to the FDA in response to a formal written request for these studies. Because such studies have not been previously undertaken and the new rules provide a significant financial incentive, written requests have been issued for pediatric studies involving more than a dozen antihypertensive agents. The FDA published a sample written request for oral antihypertensives in children and several potential study designs were presented.

Use of the peritoneal equilibration test in pediatric dialysis patients.

The peritoneal equilibration test (PET) has been used in adult peritoneal dialysis (PD) patients to determine PD efficiency and optimal dialysis prescription. To investigate its usefulness in pediatric PD patients, we performed the PET in 10 patients divided into 2 groups: 3 patients less than 2 years of age (group 1) and 7 patients aged 5 to 17 years (group 2). The PET was performed after an overnight dwell by standard protocol with an overnight dialysate sample and 6 dialysate samples during the 4 hour test. Dialysate to plasma (D/P) ratios were calculated for creatinine (Cr), urea, and protein. D/PCr over time was similar in both pediatric groups compared to adults. D/P urea over time was lower in both pediatric groups compared to published adult data. D/P protein over time was markedly increased in both pediatric groups and was highest in the smallest patients. D/P ratios are different in pediatric PD patients compared to adults. In order to be used to assess dialysis efficiency, normal values for the PET test in children need to be established.

Antihypertensive effect and pharmacokinetics of nitrendipine in children.

Nitrendipine, a new calcium-channel antagonist, was used to treat 25 children (aged 6 months to 17 years) with severe hypertension. Systolic and diastolic blood pressures (mean +/- SEM) fell from 148 +/- 2/99 +/- 2 mm Hg to 128 +/- 4/77 +/- 3 mm Hg after 24 hours and to 121 +/- 2/75 +/- 2 mm Hg after 2 weeks. No further reductions in systolic or diastolic blood pressure were observed after continued therapy. Transient reflex tachycardia occurred during the first week of therapy. Other adverse effects were uncommon and included headaches, flushing, palpitations, and edema. Pharmacokinetic parameters were estimated at steady state after an oral dose of 0.56 +/- 0.04 mg/kg in 13 children. Although absolute oral bioavailability could not be determined, estimates of the area under the plasma concentration versus time curve, the apparent peak serum concentration, and the apparent time at which the peak serum concentration occurred indicated that both the rate of absorption and oral bioavailability are variable. Coadministration of nitrendipine with food decreased the rate of absorption and may have reduced oral bioavailability. A relationship between age and the apparent plasma elimination half-life of nitrendipine was not observed. Nitrendipine, 0.25 to 0.5 mg/kg per dose administered orally every 6 to 12 hours, appeared to be an effective and safe treatment for resistant hypertension in infants and children.

Pediatric renovascular hypertension.

Renovascular disease is a frequent cause of severe hypertension in children and may result in significant morbidity or mortality. Most children presenting with renovascular hypertension have few if any symptoms, but devastating neurologic injury and congestive heart failure are still too often observed. Several new radiographic techniques have been used to detect renovascular lesions, but none has yet demonstrated consistently superior results when compared with intra-arterial digital subtraction angiography. Renal venous renin sampling, duplex ultrasonography, and captopril-enhanced renal scintigraphy may be useful diagnostic adjuncts. Therapeutic objectives include cure of hypertension and restoration or preservation of renal function. At many institutions, percutaneous transluminal angioplasty has become the treatment of choice for patients with renal transplant artery stenosis and discrete, nonostial stenoses caused by fibromuscular dysplasia. More extensive lesions generally respond well to surgical correction. Chronic pharmacologic therapy is reserved for patients who do not respond to angioplasty or in cases in which the location or extent of involvement of the renal arterial system precludes surgical revascularization. Nephrectomy is usually reserved for kidneys that have minuscule function of irreparable vascular anomalies. An individualized approach to therapy is increasingly emphasized.

Measurement of bumetanide in plasma and urine by high-performance liquid chromatography and application to bumetanide disposition.

A high-performance liquid chromatographic method for the measurement of bumetanide in plasma and urine is described. Following precipitation of proteins with acetonitrile, bumetanide was extracted from plasma or urine on a 1-ml bonded-phase C18 column and eluted with acetonitrile. Piretanide dissolved in methanol was used as the internal standard. A C18 Radial Pak column and fluorescence detection (excitation wavelength 228 nm; emission wavelength 418 nm) were used. The mobile phase consisted of methanol-water-glacial acetic acid (66:34:1, v/v) delivered isocratically at a flow-rate of 1.2 ml/min. The lower limit of detection for this method was 5 ng/ml using 0.2 ml of plasma or urine. Nafcillin, but not other semi-synthetic penicillins, was the only commonly used drug that interfered with this assay. No interference from endogenous compounds was detected. For plasma, the inter-assay coefficients of variation of the method were 7.6 and 4.4% for samples containing 10 and 250 ng/ml bumetanide, respectively. The inter-assay coefficients of variation for urine samples containing 10 and 2000 ng/ml were 8.1 and 5.7%, respectively. The calibration curve was linear over the range 5-2000 ng/ml.