The performances of the Cockcroft-Gault, modification of diet in renal disease study and chronic kidney disease epidemiology collaboration equations in predicting gentamicin clearance.

BACKGROUND: It is unclear which renal function equation, employing an isotope dilution mass spectrometry (IDMS)-aligned creatinine assay, best predicts gentamicin clearance. METHODS: The performances of the Cockcroft-Gault, Modification of Diet in Renal Disease (MDRD) Study and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations for predicting gentamicin clearances were assessed retrospectively in 240 patients treated with gentamicin during 2011-2012, when the local creatinine assay was IDMS-aligned. Comparisons were based on the percentage within 30% of gentamicin clearance (P 30) and the root-mean-square error (RMSE) of each equation. Gentamicin clearance was calculated from plasma concentrations using a one-compartment model. RESULTS: The Cockcroft-Gault equation and the CKD-EPI equation corrected for individual body surface area (BSA) were associated with the highest P 30 (69% and 67%, respectively) and lowest RMSE (39 and 36 mL/min, respectively) in the 240 patients. Correction for individual BSA improved the performances of the MDRD Study and CKD-EPI equations in patients with body mass indices <18.5 or ≥30 kg/m(2). The equations systematically underestimated gentamicin clearance as gentamicin clearance increased, with performance being inferior with gentamicin clearance ≥90 versus <90 mL/min. CONCLUSIONS: The CKD-EPI equation corrected for individual BSA, and the Cockcroft-Gault equation, provided the best estimates of gentamicin clearance. The CKD-EPI and MDRD Study equations should be corrected for individual BSA at the extremes of body size, if used for guiding gentamicin therapy. The performances of the equations were inferior in patients with higher values of gentamicin clearance.

Dosing of dabigatran etexilate in relation to renal function and drug interactions at a tertiary hospital.

BACKGROUND: Plasma concentrations of the anticoagulant dabigatran are correlated with clinical outcomes, and are affected by renal function, intestinal P-glycoprotein (P-gp) activity and stomach acidity. AIMS: To determine the adherence to dabigatran etexilate renal dosing guidelines, the frequency of co-prescription of potentially interacting drugs in patients on dabigatran, and how these related to dabigatran dosing. METHODS: A retrospective chart review of 204 patients discharged from a tertiary hospital on dabigatran etexilate over a 12-month period. Creatinine clearance, using the Cockcroft-Gault equation, was used as the surrogate of renal function in the 86 patients where this was calculable. RESULTS: Prescribed dabigatran etexilate dose rates in relation to creatinine clearance and the manufacturer's guidelines were classified as 'standard', 'low' and 'high' in 47% (40/86), 49% (42/86) and 5% (4/86) of patients respectively. Co-prescribed drugs that potentially interact with dabigatran etexilate were present in 75% (154/204) of patients and included strong P-gp inhibitors (16%, 32/204), proton-pump inhibitors (46%, 94/204) and anti-platelet drugs (47%, 95/204). Co-prescription of strong P-gp inhibitors was associated with the prescription of 'low' dose rates relative to renal function (P = 0.025). CONCLUSIONS: Few patients were dosed excessively in relation to creatinine clearance. Around 50% was prescribed with 'low' dose rates in relation to creatinine clearance, which because of the association with co-prescription of strong P-gp inhibitors may be clinically appropriate. Most patients were co-prescribed with drugs that potentially interact with dabigatran etexilate.

Comparing dose prediction software used to manage gentamicin dosing.

BACKGROUND: Current Australian guidelines recommend initiating directed therapy of gentamicin if administration exceeds 48 h. Directed doses of gentamicin require the monitoring of plasma concentrations of gentamicin to determine the 24-h area under the time course of plasma gentamicin concentrations (AUC) and a dosage prediction program, for example TCIWorks or Aladdin. However, doses calculated by such programs have not been compared with an established program. AIM: To compare the directed dosage of gentamicin calculated by TCIWorks, Aladdin and an Excel-based program, with an established program, Abbottbase. METHODS: Peak and trough plasma concentrations after the first and second administered doses of gentamicin were available from three patient groups (n = 20-23) with varying creatinine clearances (<40, 40-80, >80 mL/min). The directed dose needed to produce 24-h AUC values of 80 mg.h/L was calculated using each program. RESULTS: There was a strong correlation between the directed doses predicted by each of the three programs compared with Abbottbase, following the first administered dose (r(2) > 0.97, P < 0.0001). The mean ratio (90% confidence intervals) of these directed doses of the gentamicin were: TCIWorks/Abbottbase 106% (105-107%), Aladdin/Abbottbase 102% (101-103%) and Excel/Abbottbase 108% (106-109%). The correlations and dose ratios were also similar when comparisons were made following the second administered dose. For each of the three renal function groups, all programs yielded similar directed doses. CONCLUSIONS: The four programs used in the calculation of directed doses of gentamicin yielded similar results. Any would be suitable for use in clinical practice.

Prediction of infant drug exposure through breastfeeding: population PK modeling and simulation of fluoxetine exposure.

The likelihood of significant exposure to drugs in infants through breast milk is poorly defined, given the difficulties of conducting pharmacokinetics (PK) studies. Using fluoxetine (FX) as an example, we conducted a proof-of-principle study applying population PK (popPK) modeling and simulation to estimate drug exposure in infants through breast milk. We simulated data for 1,000 mother-infant pairs, assuming conservatively that the FX clearance in an infant is 20% of the allometrically adjusted value in adults. The model-generated estimate of the milk-to-plasma ratio for FX (mean: 0.59) was consistent with those reported in other studies. The median infant-to-mother ratio of FX steady-state plasma concentrations predicted by the simulation was 8.5%. Although the disposition of the active metabolite, norfluoxetine, could not be modeled, popPK-informed simulation may be valid for other drugs, particularly those without active metabolites, thereby providing a practical alternative to conventional PK studies for exposure risk assessment in this population.

CYP2D6 genotype and its relationship with metoprolol dose, concentrations and effect in patients with systolic heart failure.

The aims of this study were to examine the relationships between CYP2D6 genotype and metoprolol dose, S- and R-metoprolol concentrations and clinical effects in patients with systolic heart failure. Data were obtained for 52 subjects, of which 27 had 2 functional alleles (24/27, CYP2D6*1/*1), 22 had 1 functional allele (18/22, CYP2D6*1/*4) and 3 had no functional alleles (CYP2D6*4/*4). Median dose-adjusted concentrations of S-metoprolol (active) were 6.3- and 3.2-fold higher in subjects with zero or one functional allele (P=0.016 and P=0.006), respectively, compared with subjects with two functional alleles. For the R-enantiomer (inactive), these concentrations were 10.7- and 3.7-fold higher (P=0.013 and P=0.003), respectively. Despite clear gene-concentration differences, no relationships between CYP2D6 genotype and dose or clinical effects could be shown. Although the number with no functional alleles was too small (n=3) to show effects, in patients with 1 functional allele other sources of variance are likely to be obscuring differences in clinical effects.

Effect of pregnancy on the pharmacokinetics of metformin.

AIMS: To determine the effects of pregnancy on metformin pharmacokinetics. METHODS: Seven women with Type 2 diabetes mellitus taking metformin throughout pregnancy were studied on two occasions, once at 28-36 weeks gestation and once at least 8 weeks postpartum. Serum metformin concentrations were determined across a dosing interval using high-performance liquid chromatography. The areas under the serum concentration-time curve from 0 to 4 h post-dose (AUC0-4) and 0 to 8 h post-dose (AUC0-8) where possible, were compared in the pregnant and non-pregnant state. RESULTS: Metformin concentrations were lower in pregnancy in six subjects, with a mean (95% CI) AUC0-4 that was 69% (53.6, 84.8) of the postpartum value. The AUC0-4 of one subject was higher in pregnancy at 142% of the postpartum value. Overall, the mean (95% CI) AUC0-4 during pregnancy for all seven subjects was 80% (51.3, 107.8) of the postpartum value (P = 0.053, two-tailed t-test; P = 0.027, one-tailed t-test). CONCLUSION: These results are consistent with our hypothesis that the clearance of metformin increases in pregnancy as a result of enhanced renal elimination. A larger study is required to establish whether metformin dose adjustments are required in late pregnancy to maintain therapeutic effect.

Individualized drug and dose: the clinical pharmacologist's calling or curse?

1. The role of the clinical pharmacologist is to promote the rational, safe and effective use of medicines. This revolves around the notion of variability, between and within patients and between and within drugs, in terms of both pharmacokinetics and pharmacodynamics. Ideal therapeutics involves tailoring the drug and its dosing to the individual patient, taking into account this variability. 2. In the 25 years of my membership of the Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists, three themes have dominated my research: (i) drugs and breast feeding; (ii) aminoglycoside dosing; and (iii) pharmacogenetics. In all these, the research has been orientated towards identifying factors involved in variability and working towards dose individualization based on the understanding of these factors. 3. Our model for predicting drug concentrations in milk has assisted not only in estimating the safety of drug ingestion via breast milk, but also in the understanding of the processes involved in drug transfer. 4. The aminoglycoside studies have assisted in the understanding of the basis behind extended interval dosing, leading to a model for dose prediction that is widely used, especially in Australasia. 5. Pharmacogenetics is a field widely acclaimed as having a huge future in terms of individualization of drug therapy. Our early studies in this area lend only cautious support to this optimism.

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 (chi(2) = 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).

An extended interval dosing method for gentamicin in neonates.

Traditional gentamicin dosing every 8-24 h depending on age and weight in neonates does not provide the ideal concentration-time profile to both optimize the concentration-dependent killing by aminoglycosides and minimize toxicity. Fifty-three neonates were audited prospectively while receiving gentamicin 2.5 mg/kg every 8-24 h, aiming for peak concentrations (Cmax) of 6-10 mg/L and trough concentrations (Cmin) <2 mg/L. After the first dose, the mean (+/- s.d.) Cmax was 5.5 +/- 0.7 mg/L with sub-therapeutic concentrations (<6 mg/L) in 62% of patients, while the mean Cmin was >2 mg/L in 15% of the neonates. After the third dose the Cmax was 7.5 +/- 1.5 mg/L, with 17% <6 mg/L, whereas the mean Cmin was 2.2 +/- 1.1 mg/L with 49% of values >2 mg/L. An extended interval dosing method (24, 36 and 48 h) for infant weights of 0.75-5 kg was developed by simulation, and audited prospectively in 51 neonates. Prospective analysis of the extended interval dosing method showed a mean Cmax after the first dose of 13.1 +/- 3.6 mg/L, while the mean Cmin was 0.7 +/- 0.6 mg/L. Seventy-eight per cent had Cmax of >10 mg/L after the first dose. The mean area under the concentration versus time curve AUC0-24 was 93 mg*h/L (target = 100 mg*h/L). The extended interval dosing achieved higher Cmax values while ensuring that overall exposure per 24 h was acceptable. Prospective testing of the method demonstrated good predictive ability.

Distribution of R- and S-methadone into human milk during multiple, medium to high oral dosing.

AIMS: To measure the interdose milk to plasma ratio (M/P) of R- and S-methadone during multiple dosing in lactating mothers taking medium to high doses of methadone (> 40 mg daily), and to assess likely infant exposure. METHODS: Eight mother/child pairs were studied, initially during their postpartum hospital stay (immature milk), and where possible again after 15 days (mature milk). The women were on a methadone maintenance programme with daily doses of >or=40 mg day-1. Venous blood was collected at 0, 1, 2, 4, 6, 8, 12, and 24 h and milk was collected from both breasts at 0-4, 4-8, 8-12, 12-16, 16-20, and 20-24 h after dose. R- and S-methadone were quantified by h.p.l.c. The areas under the plasma and milk concentration-time curves (AUC) were estimated and M/P(AUC) was calculated. The relative infant dose of both enantiomers was estimated as the product of drug concentration in milk and an average daily milk intake of 0.15 l kg(-1). RESULTS: For immature milk (n = 8) the M/P(AUC) for R-methadone was 0.68 (95% CI 0.48, 0.89) and for S-methadone 0.38 (0.26, 0.50). For mature milk (n = 2) the M/P(AUCs) for R-methadone were 0.39 and 0.54 and for S-methadone 0.24 and 0.30, respectively. The estimated doses of R- and S-methadone that would be received by the infant via immature milk were 3.5% (2.05, 5.03%) and 2.1% (1.3, 2.8%), respectively, of the maternal dose (assuming 50% of each enantiomer in the dose). The relative infant dose for R- plus S-methadone together was 2.8% (1.7, 3.9%). CONCLUSIONS: Breastfeeding during medium to high dose methadone appears to be 'safe' according to conventional criteria because the dosage is < 10%. However because the absolute dose received by the infant is dependent on the maternal dose rate, the risk-benefit ratio should be considered for each individual case. The doses of methadone received via milk are unlikely to be sufficient to prevent the neonatal abstinence syndrome.

The therapeutic monitoring of antimicrobial agents.

AIMS: To review the basis and optimal use of therapeutic drug monitoring of antimicrobial agents. METHODS: Antimicrobial agents for which a reasonable case exists for therapeutic drug monitoring are reviewed under the following headings: pharmacokinetics, why monitor, therapeutic range, individualization of therapy, sampling times, methods of analysis, interpretative problems and cost-effectiveness of monitoring. RESULTS: There is a strong historical case for monitoring aminoglycosides. The recent move to once-daily dosing means that criteria for therapeutic drug monitoring need to be redefined. Vancomycin has been monitored routinely but many questions remain about the most appropriate approach to this. A case can be made for monitoring teicoplanin, flucytosine and itraconazole in certain circumstances. CONCLUSIONS: The approach to monitoring aminoglycosides is being redefined in the light of once daily dosing. It may be that less stringent monitoring is required in some circumstances but toxicity, especially ototoxicity, remains a problem with these drugs. Monitoring to avoid high AUCs (areas under the concentration-time curve) is recommended. The ideal method for monitoring vancomycin remains to be defined although a reasonable case exists for measuring trough concentrations, mainly to ensure efficacy. Teicoplanin is sometimes monitored to ensure efficacy while flucytosine may be monitored to avoid high concentrations associated with toxicity. Itraconazole has various pharmacokinetic problems and monitoring has been suggested to ensure that adequate concentrations are achieved.

Quinapril and its metabolite quinaprilat in human milk.

AIMS: To measure the milk to plasma ratio (M/P) of quinapril and its active metabolite quinaprilat in lactating mothers and to assess likely infant exposure. METHODS: A single dose of quinapril 20 mg was administered to six healthy mothers who had been breastfeeding their infants for at least 2 weeks. Blood was sampled for the measurement of quinapril and quinaprilat at 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 and 24 h. Milk was collected for measurement of quinapril and quinaprilat concentrations over the periods -4-0, 0-4, 4-8, 8-12, 12-18, 18-24 h. The areas under the plasma and milk concentration-time curves were estimated and an M/P ratio derived for both quinapril and quinaprilat. RESULTS: The M/P ratio for quinapril was 0.12 (95% CI 0.09,0.14). No quinapril was detected in milk after 4 h. No quinaprilat was detected in any of the milk samples. The estimated 'dose' of quinapril that would be received by the infant was 1.6% (95% CI 1.0,2.2) of the maternal dose, adjusted for respective weights. CONCLUSIONS: Quinapril appears to be 'safe' during breastfeeding according to conventional criteria, although as always, the risk:benefit ratio should be considered when it is to be given to a nursing mother.

Is cytochrome P450 2C9 genotype associated with NSAID gastric ulceration?

AIMS: The aim of this study was to explore whether genetic variation of cytochrome P450 2C9 (CYP2C9) contributes to NSAID-associated gastric ulceration. The hypothesis tested was that CYP2C9 poor metabolizer genotype would predict higher risk of gastric ulceration in patients on NSAIDs that are metabolized by CYP2C9, due to higher plasma NSAID concentrations. METHODS: Peripheral blood DNA samples from 23 people with a history of gastric ulceration attributed to NSAIDs metabolized by CYP2C9, and from 32 people on NSAIDs without gastropathy, were analysed to determine CYP2C9 genotype. RESULTS: The following genotypes were found: *1/*1 (wild type) in 70% of cases and 58% of controls, *1/*2 in 17% of cases and 29% of controls, *1/*3 in 13% of cases and 13% of controls. The difference between case and control nonwild-type genotype frequency was 11.5% (95% CI -14,37%), with the direction of the difference being against the hypothesis. No individuals with homozygote poor metaboliser genotype were identified. The differences in genotype frequencies between the two groups were not significant and the frequencies were similar to those in a large published population study. Ninety-five percent binomial confidence interval analysis confirms that there is no apparent clinically significant relationship between CYP2C9 genotype and risk of gastric ulceration although a small difference in risk in poor metabolizers cannot be excluded. CONCLUSIONS: These results do not support the hypothesis that gastric ulceration resulting from NSAID usage is linked to the poor metabolizing genotypes of CYP2C9.

Aminoglycoside adaptive resistance: importance for effective dosage regimens.

There are various pharmacodynamic features of the aminoglycosides that are thought to contribute to the benefits of once-daily administration, of which the ability to induce adaptive resistance is the least understood and discussed. However, this may be the most important characteristic conferring increased efficacy with extended interval dose administration. Adaptive resistance describes a reversible refractoriness to the bactericidal effect of an antibacterial agent. It is well documented for the aminoglycosides but has also been seen with the quinolones. It does not appear to be caused by a genetic mutational change but rather by a protective phenotypic alteration in bacterial characteristics. This includes reversible down-regulation of the active transport of aminoglycosides into gram-negative bacteria. In vitro, animal and clinical studies have shown that marked adaptive resistance of gram-negative bacteria to aminoglycosides occurs within 1-2 hours of the first dose. The duration of adaptive resistance relates directly to the half-life of elimination of the aminoglycoside. With normal human aminoglycoside pharmacokinetics, the resistance may be maximal for up to 16 hours after a single dose of aminoglycoside, followed by partial return of bacterial susceptibility at 24 hours and complete recovery at around 40 hours. With conventional dosage regimens, second and subsequent doses of aminoglycoside are given at the time of maximal resistance and this practice is also likely to reinforce the resistance. Dose administration at 24 hour intervals, or longer, may increase efficacy by allowing time for adaptive resistance to reverse.

The pharmacokinetics of oral fleroxacin and ciprofloxacin in plasma and sputum during acute and chronic dosing.

AIMS: To examine the pharmacokinetics of ciprofloxacin and fleroxacin in plasma and sputum of patients with an acute exacerbation of chronic bronchitis or bronchiectasis following the first dose and again during the third day of treatment. METHODS: Twelve patients, aged >35 years, with acute infective exacerbation of bronchitis or bronchiectasis were allocated randomly to treatment with either fleroxacin 400 mg daily or ciprofloxacin 500 mg twice daily in an open, parallel group design. Plasma and sputum were collected during the first and third days of treatment. The time course of concentrations in sputum was modelled assuming that it acted as a negligibly small compartment of distribution. RESULTS: The mean sputum to plasma ratios of both ciprofloxacin and fleroxacin were approximately 1 on both days 1 and 3. Peak concentrations of ciprofloxacin in sputum were achieved 1.6 (95% CI on mean difference 0.8-2.3) and 1.2 (0.4-1.9) h later than in plasma on day 1 and day 3, respectively (mean difference +/- 95% confidence interval). For fleroxacin, the corresponding delay in time to peak concentrations was less marked and not significant. Fleroxacin accumulated in plasma (accumulation index 1.52+/-0.07) and sputum (accumulation index 1.79+/-0.39) from day 1 to day 3. Accumulation did not occur for ciprofloxacin because the dose interval (12 h) was considerable longer than its half life (3-4 h). CONCLUSIONS: The sputum to plasma ratio of ciprofloxacin and fleroxacin is approximately 1. The time to peak concentrations of ciprofloxacin in sputum is slightly delayed compared with plasma. Fleroxacin accumulates over time in both plasma and sputum consistent with its longer half-life.

Distribution and excretion of fluoxetine and norfluoxetine in human milk.

AIMS: To characterize milk/plasma (M/P) ratio and infant dose, for fluoxetine and norfluoxetine, in breast-feeding women taking fluoxetine for the treatment of depression, and to determine the plasma concentration of these drugs in their infants. METHODS: Fourteen women (mean age 32.2 years) taking fluoxetine (mean dose 0.51 mg kg-1 day-1 ) and their infants (mean age 3.4 months) were studied. Fluoxetine and norfluoxetine in plasma and milk were measured by high-performance liquid chromatography over a 24 h dose interval in four patients, and by single point data collection in 10 patients. Infant exposure was estimated as the product of estimated milk production, and average drug concentration in milk, normalized to body weight and expressed as a percentage of the weight-adjusted maternal dose. RESULTS: Mean M/P values of 0.68 (95% CI 0.52-0.84) and 0.56 (95% CI 0.35-0.77) were calculated for fluoxetine and norfluoxetine, respectively. Mean total infant exposure (fluoxetine equivalents) was estimated to be 6.81% (range 2.15-12%) of the weight-adjusted maternal dose of fluoxetine. Contributions from fluoxetine and norfluoxetine were approximately equal. Fluoxetine (range 20-252 microgram l-1 ) was detected in five of the nine infants from whom samples were collected, and norfluoxetine (range 17-187 microgram l-1 ) was detected in seven of the nine infants. The highest of these concentrations was about 70% of the maternal plasma concentrations. CONCLUSIONS: The mean combined dose of fluoxetine and norfluoxetine transmitted to infants via breast milk is below the 10% notional level of concern. However, there was considerable interpatient variability in estimated infant dose and in some of the patients, the dose was >10%. Further, since adverse effects have been observed in breast-fed infants, careful monitoring of the infants is mandatory. Neonates exposed to these drugs in utero had higher concentrations of fluoxetine and norfluoxetine and are at greater risk of adverse effects.