Classification of orally administered drugs on the World Health Organization Model list of Essential Medicines according to the biopharmaceutics classification system.

Effects of indomethacin in premature infants with patent ductus arteriosus: Results of a national collaborative study

Cyclophosphamide is an extensively used anticancer and immunosuppressive agent. It is a prodrug undergoing a complicated process of metabolic activation and inactivation. Technical difficulties in the accurate determination of the cyclophosphamide metabolites have long hampered the assessment of the clinical pharmacology of this drug. As these techniques are becoming increasingly available, adequate description of the pharmacokinetics of cyclophosphamide and its metabolites has become possible. There is incomplete understanding on the role of cyclophosphamide metabolites in the efficacy and toxicity of cyclophosphamide therapy. However, relationships between toxicity (cardiotoxicity, veno-occlusive disease) and exposure to cyclophosphamide and its metabolites have been established. Variations in the balance between metabolic activation and inactivation of cyclophosphamide owing to autoinduction, dose escalation, drug-drug interactions and individual differences have been reported, suggesting possibilities for optimisation of cyclophosphamide therapy. Knowledge of the pharmacokinetics of cyclophosphamide, and possibly monitoring the pharmacokinetics of cyclophosphamide in individuals, may be useful for improving its therapeutic index.

Clinical Pharmacokinetics of Cyclophosphamide

Knowledge acquired of the kinetic disposition and effects of theophylline over the past 8 years has increased the clinical utility of the drug in the treatment of cardiorespiratory disorders. Although the anhydrous theophylline content varies greatly between products, there is similar excellent oral bioavailability. An average 96% (range 75 to 105%) of an uncoated theophylline tablet is absorbed, with peak concentrations occurring from 0.5 to 2.0h. Enteric coated and many sustained release preparations have poor bioavailability. Intravenous preparations of aminophylline contain from 75 to 85% theophylline by weight. Other routes of administration are not to be recommended. In plasma, some 53 to 65% of theophylline is reversibly bound to protein. Premature neonates and adults with hepatic cirrhosis have reduced binding. The apparent volume of distribution in the steady state averages 0.5L/kg body weight regardless of sex, age (1 to 87 years), history of cigarette smoking, asthma, or acute pulmonary oedema. Premature neonates and adults with acidaemia, hepatic cirrhosis or obesity tend to have larger volumes of distribution for theophylline. Theophylline is eliminated by biotransformation in the liver and urinary excretion of its metabolites. Approximately 7 to 13% is excreted unchanged in the urine by a first order process. One of the metabolites, 3-methylxanthine, which is pharmacologically active but less potent than theophylline, is eliminated by Michaelis-Menten kinetics. Removal of dietary methylxanthines can increase the rate of elimination of a single dose of theophylline. Dose dependent elimination kinetics has been suggested but not conclusively demonstrated. The plasma theophylline concentration time curve after intravenous administration fits a 2 compartment open kinetic model with a rapid a distribution phase completed within 30 to 45 minutes after an intravenous dose. The β elimination phase t½β) is quite variable and in healthy adults ranges from 3 to 13h. As the apparent volume of distribution is little altered under most conditions, variations in theophylline elimination half-life reflect alterations in plasma theophylline clearance. The predominant factors which alter theophylline clearance are age, body weight, diet, smoking habits, other drugs and cardiorespiratory or hepatic disease. The elimination of theophylline is markedly decreased in premature infants and increased in childhood. The rapid clearance in childhood decreases toward adult values in the late teens. Some authors believe old age per se decreases an individual’s capacity to eliminate theophylline. However, this may be a reflection of the inability of hepatic enzymes in the elderly to respond to factors in the diet or environment which usually stimulate theophylline clearance. The elimination half-life of theophylline is prolonged in obese subjects and maintenance doses must be calculated from ideal body weight. Theophylline clearance can be decreased by a high carbohydrate-low protein diet, as well as the ingestion of other methylxanthines such as caffeine. In contrast, a low carbohydrate-high protein diet, especially charcoal broiled meat, may enhance theophylline clearance. Theophylline clearance is markedly increased by tobacco or marihuana smoke. The rate of recovery from the stimulated state on cessation of smoking is unknown. Although there is some evidence that phenobarbitone treatment can slightly induce the hepatic metabolism of theophylline in vitro, the evidence in man for such an effect is inconclusive. The macrolide antibiotics, troleandomycin and erythromycin, are potent inhibitors of theophylline elimination. There is no evidence that uncomplicated asthma or chronic bronchitis alters theophylline clearance but, as chronic obstructive lung disease ensues with complications such as pneumonia or cor pulmonale, theophylline clearance can be markedly impaired. The elimination of theophylline is also reduced by congestive heart failure or acute pulmonary oedema. The mechanism responsible for reduced theophylline clearance in patients with cardiorespiratory disease is unclear. Reduced hepatocellular function is apparently responsible for the most marked decrease in theophylline clearance in patients with hepatic cirrhosis. It is not clear if one or several biochemical tests of liver function will allow prediction of the degree of impairment of theophylline elimination in individual patients. Reduced theophylline clearance has been observed in febrile children with acute viral exanthems. The bronchodilator effect of theophylline is related to plasma theophylline concentrations in the post-distribution period, indicating that the site of its bronchodilator activity is outside of the central kinetic compartment. Continuous improvement in forced expiratory volumes can be observed over the plasma theophylline concentration range of 5 to 20mg/L. These concentrations can reduce the frequency of asthmatic attacks, abolish exercise induced bronchospasm and increase the ventilatory response to hypoxaemia. Plasma theophylline concentrations of 5 to 20mg/L can produce concentration related increases in forearm blood flow and reductions in cerebral blood flow. The mechanism responsible for the reduction in cerebral blood flow is not clear. Peripheral venous distensibility is maximally increased at 10mg/L. Cardiac output and heart rate are variably increased. Although myocardial oxygen consumption increases, there appears to be a greater increase in oxygen delivery by increased coronary blood flow, suggesting a direct reduction of coronary vascular resistance. Pulmonary vascular resistance is reduced with increased ventilation/perfusion abnormalities. Arterial oxygen tension may decrease in asthmatic patients even though airway obstruction is relieved. Serious adverse effects are rare at plasma theophylline concentrations below 20mg/L. The most frequent adverse effects involve the gastrointestinal system (anorexia, nausea, vomiting, abdominal discomfort) and the nervous system (headache, nervousness, anxiety), which usually occur with concentrations over 15mg/L. Between 20 and 40mg/L, sinus tachycardia and atrial or ventricular arrhythmias occur with increasing frequency. Above 40mg/L, focal or generalised seizures, or cardiorespiratory arrest can occur. For rapid attainment of therapeutic plasma theophylline concentrations, a loading dose of aminophylline 5.6mg/kg can be given over 20 minutes via a peripheral vein. Although this dose is relatively safe and almost universally applicable, caution must be exercised if the patient has received theophylline in the previous 12 to 24 hour period. Maintenance doses of theophylline for intravenous or oral use should be calculated based on ideal body weight and modified for the presence of factors which alter theophylline clearance. Dose guidelines are approximations only and the wide variability in theophylline clearance between individuals and with disease makes their indiscriminant application hazardous. It is rational to begin with smaller than recommended doses and increase at intervals as tolerated until the recommended amounts are administered. In adult patients, one may limit theophylline doses to 16mg/kg daily unless a plasma theophylline concentration is obtained as a guide for further adjustment. With the proper resources, interpretive skills, and timing of plasma samples, theophylline concentrations can give the clinician sufficient information to prescribe ideal theophylline doses for an individual patient, provided the clinician searches for and recognises factors which alter theophylline clearance in that patient.

Clinical pharmacokinetics of theophylline.

This study pools published data to describe the increase in glomerular filtration rate (GFR) from very premature neonates to young adults. The data comprises measured GFR (using polyfructose, 51Cr-EDTA, mannitol or iohexol) from eight studies (n = 923) and involved very premature neonates (22 weeks postmenstrual age) to adulthood (31 years). A nonlinear mixed effects approach (NONMEM) was used to examine the influences of size and maturation on renal function. Size was the primary covariate, and GFR was standardized for a body weight of 70 kg using an allometric power model. Postmenstrual age (PMA) was a better descriptor of maturational changes than postnatal age (PNA). A sigmoid hyperbolic model described the nonlinear relationship between GFR maturation and PMA. Assuming an allometric coefficient of 3/4, the fully mature (adult) GFR is predicted to be 121.2 mL/min per 70 kg [95% confidence interval (CI) 117–125]. Half of the adult value is reached at 47.7 post-menstrual weeks (95%CI 45.1–50.5), with a Hill coefficient of 3.40 (95%CI 3.03–3.80). At 1-year postnatal age, the GFR is predicted to be 90% of the adult GFR. Glomerular filtration rate can be predicted with a consistent relationship from early prematurity to adulthood. We propose that this offers a clinically useful definition of renal function in children and young adults that is independent of the predictable changes associated with age and size.

Human renal function maturation: a quantitative description using weight and postmenstrual age

Indomethacin and renal function in premature infants with persistent patent ductus arteriosus

Digoxin immunoreactivity in cord and maternal serum and placental extracts. partial characterization of immunoreactive substances by high-performance liquid chromatography and inhibition of Na+, K+-ATPase

Salbutamol was administered to sixteen healthy male volunteers intravenously and by mouth in liquid, tablet, and capsule form using a Latin-Squares design.

Pharmacokinetics and absolute bioavailability of salbutamol in healthy adult volunteers

We have studied the disposition of cyclophosphamide, its major cytotoxic metabolite phosphoramide mustard, and the synthetic glucocorticoid dexamethasone in nine patients receiving high-dose cyclophosphamide daily for 2 days before bone marrow transplantation. The total body clearance of cyclophosphamide was observed to increase from 93 ± 27 ml/min on the first day to 178 ± 83 ml/min on the second day. This was associated with an increase in the clearance of dexamethasone from 369 ± 104 ml/min to 526 ± 123 ml/min. An increased rate of formation of phosphoramide mustard with higher peak concentrations was also seen. Simulation studies show that these changes are most likely the result of an increase in the hepatic metabolism of cyclophosphamide. These results show that high-dose cyclophosphamide causes an increase in its own clearance and that of dexamethasone through an apparent induction of hepatic-metabolizing enzymes detectable 24 hours after initial exposure to cyclophosphamide.



Clinical Pharmacology and Therapeutics (1988) 44, 622–628; doi:10.1038/clpt.1988.203

Rapid development of enhanced clearance after high‐dose cyclophosphamide

The pharmacokinetics of intravenous vancomycin was studied in 20 preterm infants (gestational age, 26.5 weeks +/- 2.6 weeks [standard deviation]; birthweight, 880 +/- 340 g). At the time of the studies their postconceptional age was 36.4 +/- 4.5 weeks. The drug was infused over 30 min in a dose between 9.2 and 18 mg/kg. A highly significant correlation existed between postconceptional age or body weight and vancomycin t1/2 and clearance. Serum creatinine concentrations correlated with vancomycin t1/2 and clearance. Serum creatinine tended to decrease with increasing postconceptional age. Based on the excellent correlation between age (or weight) and vancomycin pharmacokinetics, dose and dose-interval recommendations are presented.

S.J. Soldin

Papers

Indomethacin and renal function in premature infants with persistent patent ductus arteriosus

Digoxin immunoreactivity in cord and maternal serum and placental extracts. partial characterization of immunoreactive substances by high-performance liquid chromatography and inhibition of Na+, K+-ATPase

Pharmacokinetics and absolute bioavailability of salbutamol in healthy adult volunteers

Rapid development of enhanced clearance after high‐dose cyclophosphamide

Vancomycin pharmacokinetics and dose recommendations for preterm infants.