Objective: Funnel plots (plots of effect estimates against sample size) may be useful to detect bias in meta-analyses that were later contradicted by large trials. We examined whether a simple test of asymmetry of funnel plots predicts discordance of results when meta-analyses are compared to large trials, and we assessed the prevalence of bias in published meta-analyses. Design: Medline search to identify pairs consisting of a meta-analysis and a single large trial (concordance of results was assumed if effects were in the same direction and the meta-analytic estimate was within 30% of the trial); analysis of funnel plots from 37 meta-analyses identified from a hand search of four leading general medicine journals 1993-6 and 38 meta-analyses from the second 1996 issue of the Cochrane Database of Systematic Reviews . Main outcome measure: Degree of funnel plot asymmetry as measured by the intercept from regression of standard normal deviates against precision. Results: In the eight pairs of meta-analysis and large trial that were identified (five from cardiovascular medicine, one from diabetic medicine, one from geriatric medicine, one from perinatal medicine) there were four concordant and four discordant pairs. In all cases discordance was due to meta-analyses showing larger effects. Funnel plot asymmetry was present in three out of four discordant pairs but in none of concordant pairs. In 14 (38%) journal meta-analyses and 5 (13%) Cochrane reviews, funnel plot asymmetry indicated that there was bias. Conclusions: A simple analysis of funnel plots provides a useful test for the likely presence of bias in meta-analyses, but as the capacity to detect bias will be limited when meta-analyses are based on a limited number of small trials the results from such analyses should be treated with considerable caution. Key messages Systematic reviews of randomised trials are the best strategy for appraising evidence; however, the findings of some meta-analyses were later contradicted by large trials Funnel plots, plots of the trials9 effect estimates against sample size, are skewed and asymmetrical in the presence of publication bias and other biases Funnel plot asymmetry, measured by regression analysis, predicts discordance of results when meta-analyses are compared with single large trials Funnel plot asymmetry was found in 38% of meta-analyses published in leading general medicine journals and in 13% of reviews from the Cochrane Database of Systematic Reviews Critical examination of systematic reviews for publication and related biases should be considered a routine procedure

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Bias in meta-analysis detected by a simple, graphical test

Meta-analysis has received a mixed reception since the outset. Some people have rejected what they see as exercises in “mega-silliness,”1 while the purveyors of a highly distinguished series of meta-analyses of perinatal medical care2 have been dismissed as “an obstetrical Baader-Meinhof gang.”3 To some clinicians objecting to the findings of meta-analyses, “a tool has become a weapon.”4 At the other end of the spectrum, the application of a technique that basically consists of calculating a weighted average has been hailed as “Newtonian,”5 and it has been suggested that meta-analysis has left no place for the narrative review article.6 The truth is likely to lie somewhere between these extreme views.

#### Summary points

That meta-analysis holds potential problems can be illustrated by contrasting the conclusions of two meta-analyses comparing low molecular weight heparins and standard heparin in the prevention of thrombosis after surgery.7 8 One group concluded that “low molecular weight …

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meta-analysis bias in location and selection of studies

Significant differences that exist between the sexes affect the prevalence, incidence and severity of a broad range of diseases and conditions. Men and women also differ in their response to drug treatment. It is therefore essential to understand these reactions in order to appropriately conduct risk assessment and to design safe and effective treatments. Even from that modest perspective, how and when we use drugs can result in unwanted and unexpected outcomes. This review summarizes the sex-based differences that impact on pharmacokinetics, and includes a general comparison of clinical pharmacology as it applies to men, women and pregnant women. Sex-related or pregnancy-induced changes in drug absorption, distribution, metabolism and elimination, when significant, may guide changes in dosage regimen or therapeutic monitoring to increase its effectiveness or reduce potential toxicity. Given those parameters, and our knowledge of sex differences, we can derive essentially all factors necessary for therapeutic optimization. Since this is a rapidly evolving area, it is essential for the practitioner to review drug prescribing information and recent literature in order to fully understand the impact of these differences on clinical therapeutics.

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Sex Differences in Pharmacokinetics and Pharmacodynamics

Medicine relies on the use of pharmacologically active agents (drugs) to manage and treat disease. However, drugs are not inherently effective; the benefit of a drug is directly related to the manner by which it is administered or delivered. Drug delivery can affect drug pharmacokinetics, absorption, distribution, metabolism, duration of therapeutic effect, excretion, and toxicity. As new therapeutics (e.g., biologics) are being developed, there is an accompanying need for improved chemistries and materials to deliver them to the target site in the body, at a therapeutic concentration, and for the required period of time. In this Perspective, we provide an historical overview of drug delivery and controlled release followed by highlights of four emerging areas in the field of drug delivery: systemic RNA delivery, drug delivery for localized therapy, oral drug delivery systems, and biologic drug delivery systems. In each case, we present the barriers to effective drug delivery as well as chemical and mater...

Emerging Frontiers in Drug Delivery

Observational studies have documented that women take a variety of medications during pregnancy. It is well known that pregnancy can induce changes in the plasma concentrations of some drugs. The use of mechanistic-based approaches to drug interactions has significantly increased our ability to predict clinically significant drug interactions and improve clinical care. This same method can also be used to improve our understanding regarding the effect of pregnancy on pharmacokinetics of drugs. Limited studies suggest bioavailability of drugs is not altered during pregnancy. Increased plasma volume and protein binding changes can alter the apparent volume of distribution (Vd) of drugs. Through changes in Vd and clearance, pregnancy can cause increases or decreases in the terminal elimination half-life of drugs. Depending on whether a drug is excreted unchanged by the kidneys or which metabolic isoenzyme is involved in the metabolism of a drug can determine whether or not a change in dosage is needed during pregnancy. The renal excretion of unchanged drugs is increased during pregnancy. The metabolism of drugs catalysed by select cytochrome P450 (CYP) isoenzymes (i.e. CYP3A4, CYP2D6 and CYP2C9) and uridine diphosphate glucuronosyltransferase (UGT) isoenzymes (i.e. UGT1A4 and UGT2B7) are increased during pregnancy. Dosages of drugs predominantly metabolised by these isoenzymes or excreted by the kidneys unchanged may need to be increased during pregnancy in order to avoid loss of efficacy. In contrast, CYP1A2 and CYP2C19 activity is decreased during pregnancy, suggesting that dosage reductions may be needed to minimise potential toxicity of their substrates. There are limitations to the available data. This analysis is based primarily on observational studies, many including small numbers of women. For some isoenzymes, the effect of pregnancy on only one drug has been evaluated. The full-time course of pharmacokinetic changes during pregnancy is often not studied. The effect of pregnancy on transport proteins is unknown. Drugs eliminated by non-CYP or non-UGT pathways or multiple pathways will need to be evaluated individually. In conclusion, by evaluating the pharmacokinetic data of a variety of drugs during pregnancy and using a mechanistic-based approach, we can start to predict the effect of pregnancy for a large number of clinically used drugs. However, because of the limitations, more clinical, evidence-based studies are needed to fully elucidate the effects of pregnancy on the pharmacokinetics of drugs.

Pregnancy-induced changes in pharmacokinetics: a mechanistic-based approach.

The pharmacokinetics of theophylline following intravenous injection of aminophylline, 4 mg/kg of body weight, were determined in 30 children with asthma and in 6 normal adult volunteers. The average total clearance of theophylline was 87 ml/hr/kg in the children and 57 ml/hr/kg in the adults. The biologic half-life of theophylline in the children ranged from 1.42 to 7.85 hours, reflecting mainly pronounced interindividual differences in the elimination rate constant of the drug. There was no significant difference between the children and adults with respect to the distribution rate constants and apparent volumes of distribution of theophylline, but the elimination rate constant of the drug was considerably higher in children than in adults. Thus, children eliminate theophylline more rapidly on the average than do adults and also show pronounced interindividual differences in the elimination of the drug. Compared to adults, children tend to require relatively larger amounts of theophylline per day and the doses may have to be given at shorter intervals of time.

Pharmacokinetics of Theophylline in Children With Asthma

The purpose of this study was to determine if certain physiologic parameters (plasma bilirubin concentration and urinary excretion rate of D-glucaric acid) can be used to predict a newborn infant's ability to eliminate a phenolic drug, and particularly to predict the ability to conjugate that drug with glucuronic acid. Tweleve healthy 2- to 3-day-old full-term infants with plasma bilirubin concentrations of 1.0 to 11.6 mg/100 ml and D-glucaric acid excretion rates of 0.131 to 0.345 mg/kg/day received a single oral dose of acetaminophen, 12 mg/kg. Urine was collected serially for 48 hours and analyzed for acetaminophen, acetaminophen glucuronide, acetaminophen sulfate, and D-glucaric acid. The biologic half-life of acetaminophen was 3.5 plus or minus 0.85 hours (average plus or minus SD) as compared to average values of 1.9 to 2.2 hours observed in five reported studies on a total of 39 adults. The rate constant for acetaminophen glucuronide formation in neonates was considerably smaller, on the average, than in adults but the average rate constant for acetaminophen sulfate formation was somewhat larger than in adults. There is not statistically significant colucaric acid excretion. The results of this study suggest that the limited ability of neonates to conjugate phenolic drugs with glucuronic acid is compensated to a degree by a well-developed capability for sulfate conjugation.

Pharmacokinetics of acetaminophen in the human neonate: formation of acetaminophen glucuronide and sulfate in relation to plasma bilirubin concentration and D-glucaric acid excretion.

The serum protein binding of three weakly acidic drugs (salicylic acid, sulfisoxazole, and Phenytoin), one weak base (diazepam), and one steroid (dexamethasone) was determined in pregnant women at seven time periods during pregnancy and at two time periods post partum, as well as in a group of nonpregnant women of childbearing age. The serum free fraction values (ratio of concentrations, free to total drug) of all drugs rose during pregnancy, primarily after 15 wk of gestation, and remained elevated for at least 1 to 5 days post partum. Pregnancy had the greatest effect on protein binding of sulfisoxazole, diazepam, and salicylic acid. The magnitude of this effect is such that quantitatively significant changes in the pharmacokinetic and pharmacodynamic characteristics of certain drugs may be expected to occur during pregnancy (in addition to possible changes caused by other pregnancy-related effects such as altered activity of drug-metabolizing enzyme systems). All drugs but dexamethasone exhibited significant negative correlations between free fraction values and serum albumin concentrations during pregnancy. The serum protein binding of salicylic acid, but not the other drugs tested, was more extensive in nonpregnant women who were not taking oral contraceptives than in those who were.



Clinical Pharmacology and Therapeutics (1980) 28, 253–261; doi:10.1038/clpt.1980.158

Serum protein binding of drugs during and after pregnancy in humans.

It is now generally appreciated that there can be pronounced interindividual differences in plasma protein binding of many drugs because of genetic,13 environmental (drug interaction),11 and pathologic7 factors and aging.1 Pharmacokinetic theory has been developed to relate quantitatively the effect of changes in plasma protein binding to changes in the elimination kinetics of drugs.8,14 In the case of drugs that are eliminated almost entirely by hepatic biotransformation with linear (apparently nonsaturable) kinetics not limited by organ perfusion rate, it has been shown that the total clearance (Cl) is directly proportional to the free fraction of drug in plasma (fp), i.e.,

Effect of plasma protein and tissue binding on the biologic half-life of drugs.

Acetaminophen intoxication can cause hepatic, renal, and myocardial necrosis which is often fatal. These lesions develop very rapidly, perhaps during the first pass of the drug through the liver. In case of acute ingestion of an overdose it is therefore essential to employ measures for reducing the absorption of acetaminophen. The effect of activated charcoal on acetaminophen absorption by normal volunteers was determined as a function of the dose of charcoal, the dosage form of acetaminophen, and the charcoal-to-acetaminophen dose ratio. The results indicate that activated charcoal can be an effective antidote for acute acetaminophen intoxication, if administered promptly and in sufficient quantity.

Gerhard Levy

Papers

Pharmacokinetics of Theophylline in Children With Asthma

Pharmacokinetics of acetaminophen in the human neonate: formation of acetaminophen glucuronide and sulfate in relation to plasma bilirubin concentration and D-glucaric acid excretion.

Serum protein binding of drugs during and after pregnancy in humans.

Effect of plasma protein and tissue binding on the biologic half-life of drugs.

Effect of activated charcoal on acetaminophen absorption.