Quantitative justification for target concentration intervention - parameter variability and predictive performance using population pharmacokinetic models for aminoglycosides

Aims [1] To quantify the random and predictable components of variability for aminoglycoside clearance and volume of distribution [2] To investigate models for predicting aminoglycoside clearance in patients with low serum creatinine concentrations [3] To evaluate the predictive performance of initial dosing strategies for achieving an aminoglycoside target concentration. Methods Aminoglycoside demographic, dosing and concentration data were collected from 697 adult patients (>=20 years old) as part of standard clinical care using a target concentration intervention approach for dose individualization. It was assumed that aminoglycoside clearance had a renal and a nonrenal component, with the renal component being linearly related to predicted creatinine clearance. Results A two compartment pharmacokinetic model best described the aminoglycoside data. The addition of weight, age, sex and serum creatinine as covariates reduced the random component of between subject variability (BSVR) in clearance (CL) from 94% to 36% of population parameter variability (PPV). The final pharmacokinetic parameter estimates for the model with the best predictive performance were: CL, 4.7 l h(-1) 70 kg(-1); intercompartmental clearance (CLic), 1 l h(-1) 70 kg(-1); volume of central compartment (V-1), 19.5 l 70 kg(-1); volume of peripheral compartment (V-2) 11.2 l 70 kg(-1). Conclusions Using a fixed dose of aminoglycoside will achieve 35% of typical patients within 80-125% of a required dose. Covariate guided predictions increase this up to 61%. However, because we have shown that random within subject variability (WSVR) in clearance is less than safe and effective variability (SEV), target concentration intervention can potentially achieve safe and effective doses in 90% of patients.

Comparison of the pharmacokinetics of oxycodone and noroxycodone in male dark agouti and Sprague-Dawley rats: Influence of streptozotocin-induced diabetes

Purpose. The aims of this study are to evaluate whether cytochrome P450 (CYP)2D1/2D2-deficient dark agouti (DA) rats and/or CYP2D1/2D2-replete Sprague-Dawley (SD) rats are suitable preclinical models of the human, with respect to mirroring the very low plasma concentrations of metabolically derived oxymorphone seen in humans following oxycodone administration, and to examine the effects of streptozotocin-induced diabetes on the pharmacokinetics of oxycodone and its metabolites, noroxycodone and oxymorphone, in both rodent strains. Methods. High-performance liquid chromatography-electrospray ionization-tandem mass spectrometry was used to quantify the serum concentrations of oxycodone, noroxycodone, and oxymorphone following subcutaneous administration of bolus doses of oxycodone (2 mg/kg) to groups of nondiabetic and diabetic rats. Results. The mean (+/- SEM) areas under the serum concentration vs. time curves for oxycodone and noroxycodone were significantly higher in DA relative to SD rats (diabetic, p < 0.05; nondiabetic, p < 0.005). Serum concentrations of oxymorphone were very low (< 6.9 nM). Conclusions. Both DA and SD rats are suitable rodent models to study oxycodone's pharmacology, as their systemic exposure to metabolically derived oxymorphone (potent mu-opioid agonist) is very low, mirroring that seen in humans following oxycodone administration. Systemic exposure to oxycodone and noroxycodone was consistently higher for DA than for SD rats showing that strain differences predominated over diabetes status.

Quantifying the use of the statin antilipemic drugs: Comparisons and contrasts between Nova Scotia, Canada, and Queensland, Australia

Background: jurisdictions are developing public drug insurance systems to improve access to pharmaceuticals, cost-effective prescribing, and patient health and well-being. We compared 2 Jurisdictions with different pharmaceutical policies to determine prescribing patterns for 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (le, statins). Objective: The aim of this work was to investigate the feasibility of using available prescription admimstrative databases to compare the use of statins in Queensland, Australia, and in Nova Scotia, Canada. Methods: Data from the Nova Scotia Pharmacare Program and the Health Insurance Commission in Australia were used to obtain dispensing data. Utilization was compared for the 5-year period from 1997 through 2001, using the World Health Organization anatomic therapeutic chemical/defined daily dose (DDD) system. Results: In the year 2001, there were 177,000 beneficiaries in the public drug plan in Nova Scotia (62% aged &GE; 65 years old) and 960,000 concession beneficiaries (pensioners and social security recipients, 61% aged &GE; 65 years) in Queensland. These 2 groups were comparable. The overall utilization of statin medications increased steadily in both areas over the study period, from 50 to 205 DDD/1000 beneficiaries per day. Comparison of the 2 growth lines showed no statistically significant differences in overall statin use despite differences in brand availabilities and policies about prescribing. In the year 2001, atorvastatin was the most commonly prescribed statin in both areas, comprising 46% of statin use in Nova Scotia and 51% in Queensland. Mean doses of each statin prescribed were slightly above the DDDs. Expenditure on statins per 1000 beneficiaries and per DDD were similar in each jurisdiction, being slightly higher in Nova Scotia. Conclusions: Despite differences in pharmaceutical reimbursement systems, use of the statins was similar in Nova Scotia and Queensland. The feasibility of the methodology was demonstrated. Future studies, including comparisons of drug utilization for other classes of drugs for which drug policies may be divergent (eg, different pricing structures or prior authorization requirements), or for which less evidence for appropriate use is available, may be useful. © 2005 Excerpta Medica, Inc.

Cardiac chymase: pathophysiological role and therapeutic potential of chymase inhibitors

On release from cardiac mast cells, alpha-chymase converts angiotensin I (Ang I) to Ang II. In addition to Ang II formation, alpha-chymase is capable of activating TGF-beta 1 and IL-1 beta, forming endothelins consisting of 31 amino acids, degrading endothelin-1, altering lipid metabolism, and degrading the extracellular matrix. Under physiological conditions the role of chymase in the mast cells of the heart is uncertain. In pathological situations, chymase may be secreted and have important effects on the heart. Thus, in animal models of cardiomyopathy, pressure overload, and myocardial infarction, there are increases in both chymase mRNA levels and chymase activity in the heart. In human diseased heart homogenates, alterations in chymase activity have also been reported. These findings have raised the possibility that inhibition of chymase may have a role in the therapy of cardiac disease. The selective chymase inhibitors developed to date include TY-51076, SUN-C8257, BCEAB, NK320, and TEI-E548. These have yet to be tested in humans, but promising results have been obtained in animal models of myocardial infarction, cardiomyopathy, and tachycardia-induced heart failure. It seems likely that orally active inhibitors of chymase could have a place in the treatment of cardiac diseases where injury-induced mast cell degranulation contributes to the pathology.

Comparison of clinical trials with sildenafil, vardenafil and tadalafil in erectile dysfunction

Erectile dysfunction (ED) affects up to 50% of men, between 40 and 70 years of age. In the first major trial of sildenafil in ED, at 24 weeks, improved erections were reported by 77 and 84% of men taking sildenafil 50 and 100 mg, respectively. Subsequently, sildenafil has been reported to be effective in men with ED associated with diabetes and prostate cancer, and in psychogenic ED. Sildenafil is safe in men with coronary artery disease, provided it is not used with the nitrates (a contraindication). The most commonly reported adverse effects with sildenafil are headache, flushing and dyspepsia. Vardenafil is more potent and more selective than sildenafil at inhibiting phosphodiesterase-5. Vardenafil is similarly effective to sildenafil in the treatment of ED. The only advantage that vardenafil has over sildenafil is that it does not inhibit phosphodiesterase-6 to alter colour perception, a rare side effect which sometimes occurs with sildenafil. Tadalafil has a longer duration of action than sildenafil and vardenafil. Tadalafil is similarly effective as sildenafil in the treatment of ED. In comparison studies, tadalafil is preferred to sildenafil (50/100 mg) by men with ED, possibly because of its longer duration of action. of the phosphodiesterase inhibitors, tadalafil may displace sildenafil as the drug of choice among men with ED.

Peroxisome proliferator-activated receptor alpha expression is regulated by estrogen receptor alpha and modulates the response of MCF-7 cells to sodium butyrate

Peroxisome proliferator-activated receptors are ligand-activated transcription factors with a potential role in cancer. We investigated peroxisome proliferator-activated receptor alpha expression in breast cancer cell lines and showed a relationship between mean peroxisome proliferator-activated receptor alpha and estrogen receptor alpha mRNA levels in estrogen receptor alpha positive breast cancer cells. Transfection of estrogen receptor alpha into the estrogen receptor alpha negative cell line, MDA-MB-231 decreased peroxisome proliferator-activated receptor a mRNA and conversely inhibition of estrogen receptor alpha by ICI-182 780 in estrogen receptor a positive, MCF-7 cells increased peroxisome proliferator-activated receptor a mRNA levels. Estrogen receptor alpha levels can be modulated by histone deacetylase inhibitors and such agents are in clinical trials for cancer treatment. We found the histone deacetylase inhibitor, sodium butyrate, increased peroxisome proliferator-activated receptor alpha mRNA levels within 4 h of treatment. Peroxisome proliferator-activated receptor a modulation was independent of estrogen receptor alpha, as a similar increase was observed in the estrogen receptor a negative MDA-MB-231 cells. To further investigate the relationship between sodium butyrate and peroxisome proliferator-activated receptor alpha expression, we created an MCF-7 cell line that conditionally over-expresses human peroxisome proliferator-activated receptor alpha. Over-expression of the peroxisome proliferator-activated receptor protected MCF-7 cells from sodium butyrate-mediated inhibition of proliferation and attenuated sodium butyrate-mediated induction of histone deacetylase 3 mRNA, indicating that elevated levels of peroxisome proliferator-activated receptor alpha may reduce the sensitivity of cells to histone deacetylase inhibitors. The estrogen receptor alpha dependence of peroxisome proliferator-activated receptor alpha levels may be significant since estrogen receptor alpha negative breast cancer cells are associated with a more aggressive phenotype. Our studies also suggest that peroxisome proliferator-activated receptor alpha levels may be a marker of breast cancer cell sensitivity to histone deacetylase inhibitors. (c) 2004 Elsevier Ltd. All rights reserved.

W/O microemulsions for ocular delivery: Evaluation of ocular irritation and precorneal retention

Water-in-oil microemulsions (w/o ME) capable of undergoing a phase-transition to lamellar liquid crystals (LC) or bicontinuous ME upon aqueous dilution were formulated using Crodarnol EO, Crill 1 and Crillet 4, an alkanol or alkanediol as cosurfactant and water. The hypothesis that phase-transition of ME to LC may be induced by tears and serve to prolong precomeal retention was tested. The ocular irritation potential of components and formulations was assessed using a modified hen's egg chorioallantoic membrane test (HET-CAM) and the preocular retention of selected formulations was investigated in rabbit eye using gamma scintigraphy. Results showed that Crill 1, Crillet 4 and Crodamol EO were non-irritant. However, all other cosurfactants investigated were irritant and their irritation was dependent on their carbon chain length. A w/o ME formulated without cosurfactant showed a protective effect when a strong irritant (0.1 M NaOH) was used as the aqueous phase. Precorneal clearance studies revealed that the retention of colloidal and coarse dispersed systems was significantly greater than an aqueous solution with no significant difference between ME systems (containing 5% and 10% water) as well as o/w emulsion containing 85% water. Conversely, a LC system formulated without cosurfactant displayed a significantly greater retention compared to other formulations. (c) 2005 Elsevier B.V. All rights reserved.