Evan J. Begg

A common P-glycoprotein polymorphism is associated with nortriptyline-induced postural hypotension in patients treated for major depression

The multi-drug resistance gene ABCB1 (or MDR1) encodes a P-glycoprotein (P-gp) that regulates passage of many substances across the blood–brain barrier. The antidepressant amitriptyline and its metabolites (including nortriptyline) are substrates for P-gp, and in mice lacking P-gp, penetration of amitriptyline, but not fluoxetine, into the brain is enhanced. We reasoned that polymorphic variation of P-gp may contribute to differing responses of patients to antidepressant drugs. A single nucleotide polymorphism (SNP) of ABCB1 (3435C>T) was recently correlated with expression levels and in vivo function of P-gp. We examined this SNP in patients with major depression enrolled in a randomized antidepressant treatment trial of nortriptyline and fluoxetine, and observed a significant association between nortriptyline-induced postural hypotension and 3435C>T (χ2 = 6.78, df = 2, P = 0.034). Our results suggest that homozygosity for 3435T alleles of ABCB1 is a risk factor for occurrence of nortriptyline-induced postural hypotension (OR = 1.37, P = 0.042, 95% CI 1.01–1.86).

Drugs in human milk: clinical pharmacokinetic considerations

SummaryDrugs ingested by a lactating mother would be expected to appear in human milk to some extent and be ingested by a breast-feeding infant. Drugs pass from maternal plasma into milk by passive diffusion and are distributed within the aqueous, protein and lipid phases of milk. Distribution into milk will be affected by physiochemical characteristics of the drug: acid-base characteristics, relative protein binding in plasma and milk, and lipid solubility, as well as milk composition.The milk-to-plasma concentration ratio is the most commonly quoted index of drug distribution into human milk. However, calculation of the daily infant dose of drug ingested in milk, and from this the dose in milk relative to the maternal dose on a weight-adjusted basis, is a more relevant indicator of infant exposure to a drug. This is particularly true for drugs with a high volume of distribution, for which only a small proportion of the mother’s dose is contained within the plasma and available for distribution into milk.A better indication of infant exposure to a drug is the steady-state plasma drug concentration in a breast-feeding infant, the major determinants of which are the dose rate (via milk) and the oral availability and clearance in the infant. Although in neonates the rate of absorption may be different from adults, there is little evidence that its extent is significantly different. Clearance, however, is impaired in very young infants, particularly if premature. The decreased clearance would result in a proportional increase in steady-state plasma concentrations in the breast-feeding infant. Consideration of the dose ingested in milk and the approximate clearance in infants of different ages allows estimation of likely steady-state plasma concentrations in breast-feeding infants.From these considerations, recommendations regarding the safety of drugs during breastfeeding can be made. Drugs which are very toxic or have dose-independent toxicity should be considered separately. Recommendations regarding ‘social’ drugs such as nicotine, alcohol, caffeine and theobromine are particularly difficult, as doses are uncontrolled and vary variable.

Prediction of drug distribution into human milk from physicochemical characteristics.

SummaryDecisions about the safety of breast feeding during maternal ingestion of drugs require knowledge of the amount of drug which might be present in the milk. For many drugs this has not been studied, and mothers are usually advised against breast feeding. In many cases this is undoubtedly unnecessary, as the total dose to which the baby is exposed is often negligible. It would be very helpful, therefore, to be able to predict the approximate amount of drug which might be present in milk.Existing theory of pH partitioning enables estimation of the distribution of unbound drug. i.e. milk: plasma unbound ratios. However, these ratios are poor estimates of the concentration ratios for whole milk, because whole milk contains proteins and lipid in which drugs will distribute in amounts which depend on their particular physicochemical properties.To predict the milk: plasma concentration ratios for whole milk, the amount of drug present in the protein and lipid phases must be considered along with the unbound drug distribution. A ‘phase distribution model’ has therefore been developed which permits estimation of whole milk: plasma concentration ratios.The model requires a knowledge of the unbound drug concentration ratio, the plasma and milk unbound fractions and the milk lipid: ultrafiltrate partition coefficient. Evaluation of the model by comparison of predicted whole milk ratio values with literature milk: plasma area under the curve (AUC) ratios indicated a trend to overprediction for acidic and neutral drugs and underprediction for basic drugs. Transformation of the phase distribution equation by taking logarithms results in a relationship which can be analysed by multiple linear regression to derive predictive equations for acidic and basic drugs which take into account the relative contributions of each component of the model. Regression of the logarithms of the literature milk: plasma AUC values against the independent variables resulted in good correlations for acidic and basic drugs. The independent variables explained 93.1% and 82.9% of the variance in the values for acidic and basic drugs, respectively, with random scatter of residuals.The equations, together with those to predict unbound fractions of drug in milk and milk lipid: ultrafiltrate partition coefficients, enable the ratio of the milk: plasma AUCs to be estimated for any acidic or basic drug for which the distribution into human milk is not known, using the pKa, octanol: water partition coefficient and plasma protein binding values of the drug. The data set for neutral drugs (n = 3) was too small to develop a correlation equation.The predicted milk: plasma ratio of the 2 AUCs enables the infant dose rate to be calculated using the measured or estimated maternal steady-state plasma concentration and the volume of milk ingested.

Intratympanic Versus Intravenous Delivery of Methylprednisolone to Cochlear Perilymph

Objective: To compare methylprednisolone concentrations in the perilymph of the human ear and in plasma after intratympanic (IT) or intravenous (IV) administration. Methods: Methylprednisolone concentrations in the perilymph of patients during cochlear implantation were compared after 3 dosing strategies of methylprednisolone solution for injection (40 mg/ml): 1) IT administration of up to 40 mg was injected into the middle ear through the external auditory canal via a 27-gauge needle passed through a small anterosuperior myringotomy; 2) IV administration of 1 mg/kg was given as a single injection over 30 seconds; 3) IV administration of 10 mg/kg was infused over 30 minutes. Perilymph (single sample, ~20 μL) was sampled using a needle passed through the round window membrane, from 0.5 to 3 hours after dosing. In most patients, simultaneous blood sampling was performed. Methylprednisolone concentrations were measured by high-performance liquid chromatography with a limit of quantification of 0.001 mg/L. Results: In 39 patients studied, 33 perilymph samples were suitable for measurement, along with 26 plasma samples. Median perilymph concentrations were 6.7 mg/L (n = 18; range, 0.2-89.4 mg/L) after IT administration, 0.053 mg/L (n = 8; range, 0-0.47 mg/L) after IV injection of 1 mg/kg, and 0.2 mg/L (n = 7; range, 0.067-3.1 mg/L) after IV infusion of 10 mg/kg. The median perilymph concentrations were 126-fold higher after the IT administration than after 1 mg/kg IV (p = 0.0003) and 33-fold higher than after 10 mg/kg IV infusion (p = 0.0045). Plasma concentrations after IT administration were 16-fold lower than after IV administration of 1 mg/kg (p = 0.0006), and 136-fold lower than after IV infusion of 10 mg/kg (p = 0.0006). Conclusion: IT administration of methylprednisolone in humans results in much higher perilymph concentrations and much lower systemic concentrations than IV administration.

Once daily aminoglycoside therapy. Is it less toxic than multiple daily doses and how should it be monitored

AbstractAfter 50 years of clinical experience with the aminoglycoside agents, there is continuing debate over the most appropriate administration regimen for these drugs. In recent years, once daily administration has been used increasingly, in the hope of both improving efficacy and reducing toxicity. At least 30 controlled clinical trials have compared once versus conventional multiple daily administration. Efficacy was assessed in some, but not all, studies using clinical and/or bacteriological cure. Toxicity was generally determined using rather nonsensitive end-points such as measurement of serum creatinine for nephrotoxicity and clinically detectable hearing loss for ototoxicity.The results of individual clinical trials and subsequent meta-analyses have been variable. However, 5 of 9 meta-analyses found clinical efficacy to be significantly better with once daily administration, and in 3 of the 9 there were significantly less nephrotoxicity with once daily administration. The results were not significant for ototoxicity in any of the meta-analyses.There is debate about how therapeutic drug monitoring should be performed, and whether it is still required with once daily administration. Previous experience with the aminoglycosides, especially in patients with impaired drug clearance caused by renal impairment, suggests that monitoring is still prudent. Results from the once daily administration trials appear to support this.Various methods of monitoring and dose adjustment have been proposed. The most common is to measure a 24-hour trough concentration and to adjust the dose to maintain the trough concentration below a value of 2, 1 or 0.5 mg/L. However, this method allows for greater total aminoglycoside exposure than has been permitted with conventional dosages, increasing the likelihood of toxicity in patients with impaired aminoglycoside clearance.Other methods measure drug concentrations at a time-point or points within the dose interval (when the concentration is still measurable), and adjust the dose according to concentration-time curve nomograms or to a target area under the concentration-time curve. This allows the use of higher doses in those with high drug clearance. Furthermore, in patients with impaired clearance, drug exposure is limited to the same extent as, or less than, that with conventional multiple daily administration. To date no controlled trials have compared methods of dose-individualisation. In summary, in addition to a slight overall improvement in efficacy, once daily administration has resulted in a small reduction in nephrotoxicity. In the studies using more sensitive measures of toxicity, the differences in toxicity were greater, strengthening the case for once daily administration. Therapeutic drug monitoring is probably required with once daily administration. Methods which use mid-dosage interval concentrations to gauge drug exposure would seem to be preferable over trough concentration measurement.

Free Drug Metabolic Clearance in Elderly People

The question of whether metabolic drug clearance is decreased in elderly people has been the subject of considerable debate and is very important because clearance is a determinant of dosing. Drug clearance has been shown to be consistently impaired for flow-limited (high-clearance) drugs, but there have been conflicting results for capacity-limited (low-clearance) drugs. A limitation of the studies of capacity-limited drugs is that most have estimated clearance based on total drug concentrations (protein-bound plus free). Total drug clearance reflects both the intrinsic clearance of free drug and the extent of protein binding. Total clearance is a valid measure for capacity-limited drugs with low protein binding and appears to be consistently impaired in elderly subjects. For phenazone [antipyrine] (fraction unbound [fu] >0.9), seven studies have demonstrated statistical reductions in clearance of 20–52%. For theophylline (fu 0.6), five studies have demonstrated reductions in clearance of 22–35%. For paracetamol [acetaminophen] (fu 0.8), the clearance of which has been quoted as unchanged, four studies have demonstrated reductions in clearance of 19–35%. For highly protein-bound drugs, total clearance is not the appropriate parameter. Free drug clearance is more appropriate since it is independent of changes in protein binding. The literature was reviewed to test the hypothesis that in elderly people, capacity-limited drugs with high protein binding will show decreased free clearance even in the absence of a decrease in total clearance. For these drugs, data for free drug clearance based on measurement of actual free drug concentrations are limited, but suggest that the intrinsic metabolic clearance is impaired in elderly subjects. Four studies of naproxen (fu <0.01) have shown reduced free drug clearance of 50% or more. Two studies of valproic acid (fu 0.1–0.2) have shown reduced free clearance of 39% and 65%. Two studies of ibuprofen (fu <0.01) have shown reduced free clearance of S-ibuprofen of 21% and 28%. There is some indirect evidence for reduced clearance of the highly protein-bound drugs oxaprozin, temazepam, lorazepam, diazepam, phenytoin and warfarin, although studies measuring free concentrations are lacking. Together, the above studies support the hypothesis that the intrinsic metabolic drug clearance is impaired in elderly subjects, in the order of 20–60%, and that this effect is masked if highly protein-bound drugs are assessed using total drug clearance. If the findings are confirmed in future well-designed studies of free drug clearance, there are profound and beneficial implications for dosing of drugs in elderly people. Lower doses are likely to achieve appropriate concentrations, allowing full efficacy but decreased dose-related adverse effects.

Adaptive resistance following single doses of gentamicin in a dynamic in vitro model.

Adaptive resistance is a phenomenon recently described for Pseudomonas aeruginosa and other gram-negative bacilli following exposure to aminoglycoside antibiotics. It is a reversible form of resistance which develops within 1 to 2 h of initial exposure to an aminoglycoside and disappears several hours after removal of the antibiotic. We investigated adaptive resistance in P. aeruginosa ATCC 27853 following single doses of gentamicin by using a dynamic in vitro model which mimics in vivo pharmacokinetics. The initial peak gentamicin concentrations were 2.5, 8, and 25 mg/liter, and these were followed by an exponential decay in the concentration, with a half-life of 2.5 h. The degree of adaptive resistance was greater and the duration was longer with higher initial gentamicin concentrations. Maximal adaptive resistance occurred between 2 and 10 h following 8 mg/liter and between 2 and 16 h following 25 mg/liter. Full recovery of susceptibility occurred at approximately 36, 39, and 43 h following 2.5, 8, and 25 mg/liter, respectively, at which times the gentamicin concentrations were extremely low. Longer dosing intervals for aminoglycosides may improve efficacy by allowing time for adaptive resistance to resolve.

Studying Drugs in Human Milk: Time to Unify the Approach

The trend globally for mothers to breastfeed has highlighted the need for information on drug transfer into breast milk and the extent to which the suckling neonate may be exposed and affected. This reviewdiscusses robust study methodologies that will yield high-quality information on all aspects of this process. Methods for assessing drug transfer into breast milk are examined. The place of the milk/plasma ratio, the amount of drug in breast milk, and the volume of milk produced are discussed in the context of their utility in estimating both absolute and relative infant dose. The measurement of plasma drug concentrations and pharmacodynamic effects in the breastfed infant exposed to drugs are identified as important factors that can assist in deciding whether drug present in breast milk is a significant risk for the nursing infant.

Pharmacoeconomic Analyses of Azathioprine, Methotrexate and Prospective Pharmacogenetic Testing for the Management of Inflammatory Bowel Disease

AbstractObjectives: To compare the cost effectiveness of azathioprine (AZA), methotrexate (MTX) and no immunosuppression for maintaining remission of moderate to severe inflammatory bowel disease (IBD) in New Zealand Caucasians, and to determine whether prospective testing for poor metabolisers of AZA by genotype or phenotype is cost effective. Methods: Pharmacoeconomic models were developed to compare treatment costs and effects (QALYs) in theoretical populations of 1000 IBD patients over a 1-year period. Efficacy and tolerability profiles for AZA and MTX were taken from the literature. The costs (year 2004 values) of the drugs and treatment of adverse effects were estimated from New Zealand drug and service costs. Representations of the patients’ health-related quality of life (HR-QOL) were obtained from clinicians via the EQ-5D health state classification system and valued using the New Zealand EQ-5D social tariff. The effects of genotyping or phenotyping a population for thiopurine methyltransferase (TPMT) status were compared using the prevalence of TPMT deficiency in Caucasians, the relative risks of neutropenia and the associated costs. Results: Net cost savings (vs no immunosuppressant treatment) of approximately

Pharmacogenetic testing for drug metabolizing enzymes: is it happening in practice?

NZ2.5 million and