Darrell R. Abernethy

Effect of Age, Gender, and Obesity on Midazolam Kinetics

&NA; The effects of age, sex, and obesity on the kinetics of single intravenous (iv) and oral doses of midazolam were evaluated in healthy volunteers who received 2.5‐5 mg of iv midazolam on one occasion and 5‐10 mg orally on another. Kinetics were determined from multiple plasma midazolam concentrations measured during 24 h after dosage. Midazolam elimination half‐life (t1/2) after iv dosage was significantly prolonged in elderly (aged 60‐74 yr) versus young (24‐33 yr) males (5.6 vs. 2.1 hours, P < 0.01) and total clearance was significantly reduced (4.4 vs. 7.8 ml • min‐1 • kg‐1, P < 0.01), leading to increased systemic availability of the oral dose (50% vs. 41%, P < 0.05). However total volume of distribution calculated by the area method (Vd) (1.6 vs. 1.3 1/kg) and protein binding (3.5 vs. 3.4% unbound) did not differ between groups. Among women there were no significant differences between elderly (64‐79 yr) and young (23‐37 yr) volunteers in t1/2 (4.0 vs. 2.6 h), clearance (7.5 vs. 9.4 ml • min‐1 • kg‐1), Vd (2.1 vs. 2.0 1/kg), protein binding (3.7% vs. 3.7% unbound), or oral bioavailability (38% vs. 36%). In obese volunteers (mean weight 117 kg; 173% of ideal weight) versus control subjects of normal weight (66 kg, 95% of ideal weight) matched for age, sex, and smoking habits, midazolam Vd was increased significantly (311 vs. 114 1, P < 0.001). Vd was greater in the obese subjects even after correction for total weight (2.7 vs. 1.7 1/kg, P < 0.001), indicating disproportionate distribution of midazolam into adipose weight. Since clearance was not different between groups (472 vs. 530 ml/ min), the prolonged t1/2 in obese subjects (8.4 vs. 2.7, P < 0.001) was due to the increased Vd. The clinical consequences of age‐ and obesity‐related changes in midazolam kinetics will depend on the circumstances of administration.

Effect of Obesity on the Pharmacokinetics of Drugs in Humans

The prevalence of obesity has dramatically increased in recent years and now includes a significant proportion of the world’s children, adolescents and adults. Obesity is linked to a number of co-morbidities, the most prominent being type 2 diabetes mellitus. While many agents are available to treat these conditions, the current knowledge regarding their disposition in the obese remains limited.Over the years, both direct and indirect methodologies have been utilized to assess body composition. Commonly used direct measures include underwater weighing, skinfold measurement, bioelectrical impedance analysis and dual-energy x-ray absorptiometry. Unfortunately, these methods are not readily available to the majority of clinicians. As a result, a number of indirect measures to assess body composition have been developed. Indirect measures rely on patient attributes such as height, bodyweight and sex. These size metrics are often utilized clinically and include body mass index (BMI), body surface area (BSA), ideal bodyweight (IBW), percent IBW, adjusted bodyweight, lean bodyweight (LBW) and predicted normal weight (PNWT).An understanding of how the volume of distribution (Vd) of a drug changes in the obese is critical, as this parameter determines loading-dose selection. The Vd of a drug is dependent upon its physiochemical properties, the degree of plasma protein binding and tissue blood flow. Obesity does not appear to have an impact on drug binding to albumin; however, data regarding α1-acid glycoprotein binding have been contradictory. A reduction in tissue blood flow and alterations in cardiac structure and function have been noted in obese individuals. At the present time, a universal size descriptor to describe the Vd of all drugs in obese and lean individuals does not exist.Drug clearance (CL) is the primary determinant to consider when designing a maintenance dose regimen. CL is largely controlled by hepatic and renal physiology. In the obese, increases in cytochrome P450 2E1 activity and phase II conjugation activity have been observed. The effects of obesity on renal tubular secretion, tubular reabsorption, and glomerular filtration have not been fully elucidated. As with the Vd, a single, well validated size metric to characterize drug CL in the obese does not currently exist. Therefore, clinicians should apply a weight-normalized maintenance dose, using a size descriptor that corrects for differences in absolute CL between obese and non-obese individuals.The elimination half-life (t½) of a drug depends on both the Vd and CL. Since the Vd and CL are biologically independent entities, changes in the t½ of a drug in obese individuals can reflect changes in the Vd, the CL, or both.This review also examines recent publications that investigated the disposition of several classes of drugs in the obese — antibacterials, anticoagulants, antidiabetics, anticancer agents and neuromuscular blockers.In conclusion, pharmacokinetic data in obese patients do not exist for the majority of drugs. In situations where such information is available, clinicians should design treatment regimens that account for any significant differences in the CL and Vd in the obese.

Pharmacokinetics and Clinical Effectiveness of Methylphenidate

Methylphenidate is prescribed for over 90% of children in the US diagnosed as having attention-deficit hyperactivity disorder (ADHD). Although ADHD has been widely studied, the use of methylphenidate in ADHD still poses a number of unresolved questions, including its pharmacodynamic characteristics (drug concentration-effect relationship) and the effect of long term treatment on the patient’s psychopathology later in life. The objective of this review is to provide an analysis of the pharmacokinetic-pharmacodynamic properties and therapeutic effectiveness of methylphenidate that may help to answer some of these questions.Methylphenidate has 2 chiral centres, but the drug used in therapy comprises only the threo pair of enantiomers. d-threo-Methylphenidate is more potent than the l-enantiomer. Methylphenidate is administered as a racemic mixture that undergoes stereoselective clearance.Methylphenidate is a short-acting stimulant with a duration of action of 1 to 4 hours and a pharmacokinetic half-life of 2 to 3 hours. Maximum drug concentration after oral administration occurs at about 2 hours. Methylphenidate is absorbed well from the gastrointestinal tract and easily passes to the brain.Methylphenidate is efficacious for short term treatment for children with ADHD. Its mechanism of action is not understood, but may be associated with its influence on multiple neurotransmitters, especially the release and reuptake of dopamine in the striatum.There is marked individual variability in the dose-response relationship for methylphenidate, and therefore dosage must be titrated for optimal effect and avoidance of toxicity in each child. It is unclear whether this variability is predominantly pharmacokinetic or pharmacodynamic. If variable stereoselective metabolism occurs clinically, therapeutic drug monitoring of methylphenidate will require the application of chiral assay methods for the analysis of the active component, d-threo-methylphenidate.It is difficult to predict which children will have a favourable response to methylphenidate. Nonetheless, several studies have been published linking the severity of ADHD in children with improved clinical response to methylphenidate. The use of individual single-blind medication trials may be a practical solution to this problem. Additionally, the targeted condition warrants careful consideration, since different conditions (e.g. misbehaviour or poor academic performance) may require different regimens. Further studies of the relationship between the pharmacokinetic and pharmacodynamic properties of methylphenidate are required to allow the development of optimal dosage regimens.

Drug disposition in obese humans. An update

SummaryDrug disposition for many drugs has now been studied in obese individuals and some general conclusions can be drawn. Absorption of drugs evaluated to date is unchanged due to obesity. Apparent volume of distribution is greatly increased for some drugs including most benzodiazepines, thiopentone, phenytoin, verapamil and lignocaine (lidocaine). Modest increases in volume of distribution have been noted for methylxanthines, aminoglycosides, vancomycin, ibuprofen, prednisolone and heparin. Distribution of digoxin, cimetidine and procainamide is unchanged in obesity. The mechanism for the increased distribution of some drugs and unchanged distribution of others in obesity is unclear at present. It may be in part due to the lipophilic character of the drug molecule; however, other complex and as yet poorly understood factors contribute to the variability in drug distribution in obese patients.Protein binding of drugs bound to albumin is not dramatically changed in obesity. In contrast, some studies report that drugs bound to α1-acid glycoprotein (AAG) may have increased binding that is related to increased serum AAG concentration; however, this is not a consistent finding.Oxidative drug biotransformation is minimally changed in obesity with the exceptions of ibuprofen and prednisolone, for which clearance increases as a highly correlated function of total bodyweight. Drug conjugation uniformly increases as a function of bodyweight in obesity, with paracetamol (acetaminophen), lorazepam and oxazepam having been studied. Drug acetylation may be unchanged in obesity, with only procainamide evaluated at this time. High clearance drugs, including lignocaine, verapamil and midazolam, have no change in clearance in obese individuals compared to normal bodyweight controls. Renal clearance of drugs is little changed for some drugs evaluated (digoxin, cimetidine), and increased for others (aminoglycosides, unmetabolised procainamide). Characterisation of appropriate animal models of obesity is underway to clarify the mechanisms for these in vivo pharmacokinetic observations in obese man. Two models, the Zucker obese and the obese cafeteria-fed male Sprague-Dawley rat, have provided preliminary physiological pharmacokinetic data with evaluations of theophylline, phenobarbitone and verapamil. The Zucker genetically obese rat may be somewhat limited as a model due to impairment in renal function and impairment in capacity for regulation of cytochrome P-450 activity in obese animals that differs from heterozygous lean Zucker rats. Limitations of the cafeteria-fed Sprague-Dawley rat model of obesity identified to date are that only male rats will eat to a significant extent of obesity, the alteration in animal diet required to achieve obesity is difficult to properly control in pharmacokinetic studies in which dietary alteration in man and animals is well known to change oxidative drug clearance, and that at least 3 months of feeding the specialised diet are required to achieve bodyweight at least 40% in excess of control animals. With further identification and understanding of the limitations of these models, a mechanistic understanding of pharmacokinetic alterations associated with human obesity may be forthcoming.

Caloric restriction and intermittent fasting alter spectral measures of heart rate and blood pressure variability in rats

Dietary restriction (DR) has been shown to increase life span, delay or prevent age‐associated diseases, and improve functional and metabolic cardiovascular risk factors in rodents and other species. To investigate the effects of DR on beat‐to‐beat heart rate and diastolic blood pressure variability (HRV and DPV) in male Sprague‐Dawley rats, we implanted telemetric transmitters and animals were maintained on either intermittent fasting (every other day feeding) or calorie‐restricted (40% caloric reduction) diets. Using power spectral analysis, we evaluated the temporal profiles of the low‐and high‐frequency oscillatory components in heart rate and diastolic blood pressure signals to assess cardiac autonomic activity. Body weight, heart rate, and systolic and diastolic blood pressure were all found to decrease in response to DR. Both methods of DR produced decreases in the low‐frequency component of DPV spectra, a marker for sympathetic tone, and the high‐frequency component of HRV spectra, a marker for parasympathetic activity, was increased. These parameters required at least 1 month to become maximal, but returned toward base‐line values rapidly once rats resumed ad libitum diets. These results suggest an additional cardiovascular benefit of DR that merits further studies of this potential effect in humans.‐Mager, D. E., Wan, R., Brown, M., Cheng, A., Wareski, P., Abernethy, D. R., Mattson, M. P. Caloric restriction and intermittent fasting alter spectral measures of heart rate and blood pressure variability in rats. FASEB J. 20, 631–637 (2006)

Impairment of caffeine clearance by chronic use of low-dose oestrogen-containing oral contraceptives.

SummaryThe effect of chronic (>3 months) administration of low-dose oestrogen-containing (<50 µg oestrogen) oral contraceptives (OCS) on the pharmacokinetics of caffeine has been examined in a treated females matched with 9 non-smoking, drug-free, healthy control females of similar age, weight and ethnic origin. Each subject received 162 mg caffeine base orally after an overnight fast. OCS subjects had a prolonged elimination half-life of caffeine, (mean 7.88 h vs 5.37 h in the controls). This was the result of marked impairment of the plasma clearance of caffeine (1.05 vs 1.75 ml/min/kg, respectively) with no change in apparent volume of distribution (0.685 in OCS vs 0.750 l/kg in the control group). The absorption parameters determined were peak plasma caffeine concentration (3.99 vs 4.09 µg/ml) and time to peak concentration after drug administration (1.52 vs 0.79), which was moderately prolonged in OCS users. Thus, caffeine clearance, previously reported to be a specific marker of cytochrome P-448 activity in man, is decreased by chronic OCS use. This suggests that OCS may cause significant impairment of this enzyme activity as assessed in vivo. With chronic caffeine consumption, OCS users are predicted to have an increased steady-state plasma caffeine concentration as compared to non-OCS users.

High‐Risk Prescribing and Incidence of Frailty Among Older Community‐Dwelling Men

Evidence about the association between treatment with high–risk medicines and frailty in older individuals is limited. We investigated the relationship between high–risk prescribing and frailty at baseline, as well as 2–year incident frailty, in 1,662 men ≥70 years of age. High–risk prescribing was defined as polypharmacy (≥5 medicines), hyperpolypharmacy (≥10 medicines), and by the Drug Burden Index (DBI), a dose–normalized measure of anticholinergic and sedative medicines. At baseline, frail participants had adjusted odds ratios (ORs) of 2.55 (95% confidence interval, CI: 1.69–3.84) for polypharmacy, 5.80 (95% CI: 2.90–11.61) for hyperpolypharmacy, and 2.33 (95% CI: 1.58–3.45) for DBI exposure, as compared with robust participants. Of the 1,242 men who were robust at baseline, 6.2% developed frailty over two years. Adjusted ORs of incident frailty were 2.45 (95% CI: 1.42–4.23) for polypharmacy, 2.50 (95% CI: 0.76–8.26) for hyperpolypharmacy, and 2.14 (95% CI: 1.25–3.64) for DBI exposure. High–risk prescribing may contribute to frailty in community–dwelling older men.

The pharmacokinetic profile of amlodipine

Amlodipine, a dihydropyridine calcium antagonist, was synthesized in an attempt to develop a compound with a pharmacokinetic profile characteristic of this class, which would also have an increased oral bioavailability and extended clearance time. A single intravenous dose of 10 mg resulted in an absolute bioavailability of 64% and a calculated elimination half-life of 34 hours. The pharmacokinetic profile of oral doses showed similar changes. These results were significantly different from those seen with most other dihydropyridines (elimination half-life of 3 to 10 hours and absolute bioavailability of 10% to 30%) and nondihydropyridine calcium antagonists (elimination half-life 3 to 6 hours and low absolute bioavailability). With chronic oral dosing of amlodipine once daily for 14 days, support was provided for the linearity of amlodipines pharmacokinetics and absence of such with chronic oral dosing with verapamil, diltiazem, and nifedipine. In the elderly population, elimination half-life of 5 mg oral doses is significantly prolonged (48 vs 35 hours; p less than 0.025) suggesting decreased oral clearance or increased bioavailability. Comparison of the pharmacokinetics of amlodipine in patients with chronic stable angina pectoris with the profile in healthy volunteers suggested that clearance is not altered in patients with chronic stable angina, steady state being reached 6 to 12 hours after administration of the drug. In patients with cirrhosis, elimination half-life is significantly prolonged (60 vs 34 hours; p less than 0.01) suggesting that there is a greater accumulation of amlodipine in patients with severe liver disease than in individuals with normal hepatic function.(ABSTRACT TRUNCATED AT 250 WORDS)

The Pharmacokinetics of Midazolam in Chronic Renal Failure Patients

Fifteen patients with chronic renal failure (CRF) were given midazolam 0.2 mg/kg iv over 15 s. All but one lost consciousness in a time ranging from 22–100 s (mean ± SD was 55 ± 26 s) after drug administration. Patients regained consciousness from 6–105 min (mean 53 ± 32) after drug administration. The calculated mean plasma level of midazolam at arousal was 81 ± 47 ng/ml. Pharmacokinetics parameters were determined from midazolam plasma levels measured in 16 consecutive venous blood samples. The pharmacokinetic parameters in CRF patients were compared with those of healthy volunteers matched for age, sex, and body size with the CRF patients. Protein binding was determined by equilibrium dialysis. CRF patients had a significantly higher (P ≤ 0.005) plasma-free drug fraction (6.5% ± 0.7) compared with the control patients (3.9% ± 0.1). Total (bound plus unbound) kinetics differed in the two groups: volume of distribution 3.8 ± .3 1/kg in CRF patients versus 2.2 ± .2 1/kg in controls (P ≤ 0.001), and clearance 11.4 ± 1.6 ml·min-1-1·kg-1 in CRF patients versus 6.7 ± 0.9 ml·min-1kg-1 in controls (P ≤ 0.02). When kinetic parameters were corrected for protein binding, CRF patients unbound volume of distribution (63.5 ± 6.8 1/kg) and free drug clearance (189 ± 29 ml·min-1·kg-1) were not different from the control groups volume of distribution (55.6 ± 5.7 1/kg) and free drug clearance (176 ± 24 ml·min-1·kg-1). Midazolam elimination half-life was almost identical in both groups; in CRF it was 4.58 ± 0.75 h and 4.93 ± 1.08 h in healthy controls. Because CRF does not alter the distribution, elimination, or clearance of unbound midazolam, changes in the pharmacodynamic profile of midazolam in CRF patients, if they exist, are more likely due to inherent alterations in drug sensitivity than to pharmacokinetic changes.

Impairment of Diazepam Metabolism by Low-Dose Estrogen-Containing Oral-Contraceptive Steroids

The longterm use of low-dose estrogen containing oral contraceptives (OCs) and its impairment of diazepam clearance is reported. 8 healthy women, ranging in age from 52 to 72 years, participated in the study. All of the women had been taking low-dose estrogen containing OCs for more than 3 months. 1 of the subjects was a cigarette smoker. 8 healthy controls (all nonsmokers) who were not using OCs also participated. They ranged in age from 27-31 years. Diazepam (10 mg) was given by intravenous infusion over 15-30 seconds. Venous blood samples were drawn into heparinized tubes before the infusion, at the end of the infusion, at 5, 15, 30, and 45 minutes, at 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours, and daily for 7 days after the infusion. Plasma concentrations of diazepam after intravenous infusion were analyzed by weighted iterative nonlinear least-squares regression techniques. The volume of distribution of diazepam was not significantly different between the groups, but the apparent elimination half-life of diazepam was significantly longer and the total metabolic clearance significantly less in the OC users than in the control group. The differences were not confounded by variations in protein binding. The mean diazepam free fraction was identical in the 2 groups. The clinical result of the decrease in diazepam clearance reported here would be increased steady-state plasma diazepam concentration after longterm use at a given daily dose, with the potential for increasing the clinical effects of diazepam in this population.