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Alendronate (alendronic acid; 4-amino-1-hydroxybutylidene bisphosphonate) has demonstrated effectiveness orally in the treatment and prevention of postmenopausal osteoporosis, corticosteroid-induced osteoporosis and Paget’s disease of the bone. Its primary mechanism of action involves the inhibition of osteoclastic bone resorption. The pharmacokinetics and pharmacodynamics of alendronate must be interpreted in the context of its unique properties, which include targeting to the skeleton and incorporation into the skeletal matrix. Preclinically, alendronate is not metabolised in animals and is cleared from the plasma by uptake into bone and elimination via renal excretion. Although soon after administration the drug distributes widely in the body, this transient state is rapidly followed by a nonsaturable redistribution to skeletal tissues. Oral bioavailability is about 0.9 to 1.8%, and food markedly inhibits oral absorption. Removal of the drug from bone reflects the underlying rate of turnover of the skeleton. Renal clearance appears to involve both glomerular filtration and a specialised secretory pathway. Clinically, the pharmacokinetics of alendronate have been characterised almost exclusively based on urinary excretion data because of the extremely low concentrations achieved after oral administration. After intravenous administration of radiolabelled alendronate to women, no metabolites of the drug were detectable and urinary excretion was the sole means of elimination. About 40 to 60% of the dose is retained for a long time in the body, presumably in the skeleton, with no evidence of saturation or influence of one intravenous dose on the pharmacokinetics of subsequent doses. The oral bioavailability of alendronate in the fasted state is about 0.7%, with no significant difference between men and women. Absorption and disposition appear independent of dose. Food substantially reduces the bioavailability of oral alendronate; otherwise, no substantive drug interactions have been identified. The pharmacokinetic properties of alendronate are evident pharmacodynamically. Alendronate treatment results in an early and dose-dependent inhibition of skeletal resorption, which can be followed clinically with biochemical markers, and which ultimately reaches a plateau and is slowly reversible upon discontinuation of the drug. These findings reflect the uptake of the drug into bone, where it exerts its pharmacological activity, and a time course that results from the long residence time in the skeleton. The net result is that alendronate corrects the underlying imbalance in skeletal turnover characteristic of several disease states. In women with postmenopausal osteoporosis, for example, alendronate treatment results in increases in bone mass and a reduction in fracture incidence, including at the hip.

Patients on long term valproate treatment exhibit unusual fluctuations in steady-state plasma levels of valproic acid. In order to delineate the underlying mechanisms of these fluctuations, 2 studies were undertaken. In the oral study, 6 epileptic patients received enteric-coated sodium valproate tablets (on a bid regimen for at least 1 month) and plasma levels were monitored on an hourly basis during 24 hours. In the intravenous study, 5 patients received first an intravenous bolus dose (800mg) of sodium valproate followed a week later by a combination intravenous loading dose/constant rate infusion for 36 hours. Plasma valproic acid concentrations were monitored hourly during the infusion study. In the oral study, valproic acid concentrations in all subjects continued to decay for 5 to 6 hours following the 8pm dose. The mean fluctuation in concentrations during 24 hours was 112.8 ± 31.6%. Consecutive fasting levels were not reproducible. In the intravenous study, small but significant oscillations were present at steady-state; fluctuations ranged from 22 to 34%. However, no circadian rhythm was apparent. On the basis of these findings, it appears that the value of a single fasting sample during therapeutic monitoring of valproic acid is questionable. For an accurate evaluation of valproic acid plasma levels, an average concentration based upon several daily determinations should be performed.

Malaria is a serious parasitic infection, which affects millions of people worldwide. As pregnancy has been shown to alter the pharmacokinetics of many medications, the efficacy and safety of antimalarial drug regimens may be compromised in pregnant women. The objective of this review is to systematically review published literature on the pharmacokinetics of antimalarial agents in pregnant women. A search of MEDLINE (1948-May 2011), EMBASE (1980-May 2011), International Pharmaceutical Abstracts (1970-May 2011), Google and Google Scholar was conducted for articles describing the pharmacokinetics of antimalarials in pregnancy (and supplemented by a bibliographic review of all relevant articles); all identified studies were summarized and evaluated according to the level of evidence, based on the classification system developed by the US Preventive Services Task Force. Identified articles were included in the review if the study had at least one group that reported at least one pharmacokinetic parameter of interest in pregnant women. Articles were excluded from the review if no pharmacokinetic information was reported or if both pregnant and non-pregnant women were analysed within the same group. For quinine and its metabolites, there were three articles (one level II-1 and two level III); for artemisinin compounds, two articles (both level III); for lumefantrine, two articles (both level III); for atovaquone, two articles (both level III); for proguanil, three articles (one level II-1 and two level III); for sulfadoxine, three articles (all level II-1); for pyrimethamine, three articles (all level II-1); for chloroquine and its metabolite, four articles (three level II-1 and one level II-3); for mefloquine, two articles (one level II-1 and one level III); and for azithromycin, two articles (one level II-1 and one level III). Although comparative trials were identified, most of these studies were descriptive and classified as level III evidence. The main findings showed that pharmacokinetic parameters are commonly altered in pregnancy for the majority of recommended agents. Importantly, first-line regimens of artemisinin-based compounds, lumefantrine, chloroquine and pyrimethamine/sulfadoxine may undergo significant changes that could decrease therapeutic efficacy. These changes are usually due to increases in the apparent oral clearance and volume of distribution that commonly occur in pregnant women, and may result in decreased exposure and increased therapeutic failure. In order to assess the clinical implications of these changes and to provide safe and effective dosage regimens, there is an immediate need for dose-optimization studies of all recommended first- and second-line agents used in pregnant women with malaria.

Ultra rapid lispro (URLi) is a novel insulin lispro formulation developed to more closely match physiological insulin secretion and improve postprandial glucose control. This pooled analysis compared the pharmacokinetics and glucodynamics between URLi and Humalog® in healthy subjects and patients with type 1 or type 2 diabetes mellitus. The analysis included four randomized, double-blind, crossover, single-dose studies (healthy subjects [n = 74], patients with type 1 diabetes [n = 78], and type 2 diabetes [n = 38]) evaluating subcutaneous doses of 7, 15, or 30 U of URLi and Humalog during an 8- to 10-h euglycemic clamp procedure. The pooled analysis showed an ~ 5-min faster onset of appearance, an ~8-fold greater exposure in the first 15 min, a 43% reduction in exposure beyond 3 h, and a 68-min shorter exposure duration with URLi vs Humalog across all study populations and dose range. Compared with Humalog, URLi had a 10-min faster onset of action, a 3-fold greater insulin action in the first 30 min, a 35% reduction in insulin action beyond 4 h, and a 44-min shorter duration of action across all populations and dose range. Overall exposure and insulin action were similar between URLi and Humalog for each dose level and study population. Across the studied populations and dose range, URLi consistently demonstrated a faster absorption, reduced late exposure, and overall shorter exposure duration compared with Humalog. Similarly, URLi demonstrated earlier insulin action while reducing late insulin action and shorter insulin action compared with Humalog across the study populations and dose range. NCT02942654 (registered: 21 October, 2016), NCT03286751 (registered: 15 September, 2017), NCT03166124 (registered: 23 May, 2017), and NCT03305822 (registered: 5 October, 2017).