AimTo develop a population pharmacokinetic model for mycophenolic acid in adult kidney transplant recipients, quantifying average population pharmacokinetic parameter values, and between-and within-subject variability and to evaluate the influence of covariates on the pharmacokinetic variability. Methods Pharmacokinetic data for mycophenolic acid and covariate information were previously available from 22 patients who underwent kidney transplantation at the Princess Alexandra Hospital. All patients received mycophenolate mofetil 1 g orally twice daily. A total of 557 concentration-time points were available. Data were analysed using the first-order method in NONMEM (version 5 level 1.1) using the G77 FORTRAN compiler.Results The best base model was a two-compartment model with a lag time (apparent oral clearance was 27 l h -1 , and apparent volume of the central compartment 98 l). There was visual evidence of complex absorption and time-dependent clearance processes, but they could not be successfully modelled in this study. Weight was investigated as a covariate, but no significant relationship was determined. Conclusions The complexity in determining the pharmacokinetics of mycophenolic acid is currently underestimated. More complex pharmacokinetic models, though not supported by the limited data collected for this study, may prove useful in the future. The large between-subject and between-occasion variability and the possibility of nonlinear processes associated with the pharmacokinetics of mycophenolic acid raise questions about the value of the use of therapeutic monitoring and limited sampling strategies.

BackgroundFibromyalgia is a chronic widespread pain condition a ecting millions of people worldwide. Current pharmacotherapies are o en ine ective and poorly tolerated. Combining di erent agents could provide superior pain relief and possibly also fewer side e ects. ObjectivesTo assess the e icacy, safety, and tolerability of combination pharmacotherapy compared to monotherapy or placebo, or both, for the treatment of fibromyalgia pain in adults. Search methodsWe searched CENTRAL, MEDLINE, and Embase to September 2017. We also searched reference lists of other reviews and trials registries. Selection criteriaDouble-blind, randomised controlled trials comparing combinations of two or more drugs to placebo or other comparators, or both, for the treatment of fibromyalgia pain. Data collection and analysisFrom all studies, we extracted data on: participant-reported pain relief of 30% or 50% or greater; patient global impression of clinical change (PGIC) much or very much improved or very much improved; any other pain-related outcome of improvement; withdrawals (lack of e icacy, adverse events), participants experiencing any adverse event, serious adverse events, and specific adverse events (e.g. somnolence and dizziness). The primary comparison was between combination and one or all single-agent comparators. We also assessed the evidence using GRADE and created a 'Summary of findings' table. Main resultsWe identified 16 studies with 1474 participants. Three studies combined a non-steroidal anti-inflammatory drug (NSAID) with a benzodiazepine (306 participants); two combined amitriptyline with fluoxetine (89 participants); two combined amitriptyline with a di erent agent (92 participants); two combined melatonin with an antidepressant (164 participants); one combined carisoprodol, paracetamol (acetaminophen), and ca eine (58 participants); one combined tramadol and paracetamol (acetaminophen) (315 participants); one combined malic acid and magnesium (24 participants); one combined a monoamine oxidase inhibitor with 5hydroxytryptophan (200 participants); and one combined pregabalin with duloxetine (41 participants). Six studies compared the combination of multiple agents with each component alone and with inactive placebo; three studies compared combination Combination pharmacotherapy for the treatment of fibromyalgia in adults (Review)

Pathogenic accumulation of calcium (Ca) and phosphate (PO ) in vasculature is a sentinel of advancing cardiovascular disease in chronic kidney disease (CKD). This study sought to characterize acute distribution patterns of radiolabeled PO and Ca in cardiovascular tissues of rats with CKD (0.25% dietary adenine). The disposition of PO and Ca was assessed in blood and 36 tissues after a 10-minute intravenous infusion of one of the following: (i) PO pulse + tracer PO ; (ii) PO pulse + tracer Ca; or (iii) saline + tracer Ca in CKD and non-CKD animals. After the infusion, PO in blood was elevated (2.3× at 10 minutes, 3.5× at 30 minutes, p < 0.05) in CKD compared with non-CKD. In contrast, there was no difference in clearance of Ca from the blood. Compared with controls, CKD rats had a markedly increased PO incorporation in several tissues (skeletal muscle, 7.8×; heart, 5.5×), but accrual was most pronounced in the vasculature (24.8×). There was a significant, but smaller, increase in Ca accrual in the vasculature of CKD rats (1.25×), particularly in the calcified rat, in response to the acute phosphate load. Based on the pattern of tissue uptake of PO and Ca, this study revealed that an increase in circulating PO is an important stimulus for the accumulation of these minerals in vascular tissue in CKD. This response is further enhanced when vascular calcification is also present. The finding of enhanced vascular mineral deposition in response to an acute PO pulse provides evidence of significant tissue-specific susceptibility to calcification. © 2018 American Society for Bone and Mineral Research.

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