Aims To conduct a randomized, parallel group comparison of the population pharmacokinetics of the two methylprednisolone (MP) prodrugs Promedrol (MP suleptanate) and Solu‐Medrol (MP succinate) in patients hospitalized with acute asthma. Methods Ninety volunteers were included in the pharmacokinetic analysis. Each volunteer received a dosage regimen of 40 mg (MP equivalents) i.v. 6 hourly for 48 h. The bio‐conversion and disposition of a 40 mg (MP equivalent) i.v. dose of either MP suleptanate or MP succinate to MP was modelled as a first order input, and a mono‐exponential elimination phase. Results Population modelling indicated that the only difference in MP pharmacokinetics between MP suleptanate and MP succinate was in the input rate constant (66.0 h −1 vs 5.5 h −1 respectively). Based on individual Bayesian estimates, the exposure of patients to MP was marginally lower for MP suleptanate although the parameter estimates were not significantly different for half‐life (2.7 h vs 3.0 h), steady‐state AUC (2007.0 ng ml −1 h vs 2321.0 ng ml −1 h) and steady‐state C max (698.4 ng ml −1 vs 647.8 ng ml −1 ) for MP suleptanate and MP succinate respectively. Conclusions It was concluded that for the multiple dosage regimen used in patients with acute asthma the systemic exposure to MP following dosing with MP suleptanate is similar to that arising from MP succinate. In addition the differences in the pharmacokinetics for the prodrugs resulted in only a small difference in the relative bioavailability of MP for MP suleptanate (0.94) compared with MP succinate.
We read with interest the recent article on the systemic bioavailability of hydrofluoroalkane (HFA) formulations containing fluticasone propionate and salmeterol by Clearie et al. [1]. The authors concluded that the generic and innovator products were clinically interchangeable despite an incomplete evaluation of the in vitro data and a failure to demonstrate bioequivalence for all the primary PK/PD endpoints. One of the main findings was a lack of correlation between in vitro fine particle dose data and in vivo PK/PD outcomes [1]. However, it is not clear whether this observation was confounded by the methodology used. Although not mentioned by the authors, this lack of in vivo/in vitro correlation has been reported previously for a study comparing two combination dry powder inhalers containing fluticasone propionate (FP) and salmeterol (SM) [2] and discussed extensively [3–5]. Although interesting, in both cases the lack of in vivo/in vitro correlation is not a justification for less stringent criteria for in vivo equivalence. The authors gave no details of the generic formulation and device being tested and insufficient details of the in vitro testing. In reporting the in vitro data the authors describe the test (T) and reference (R) products as having similar overall fine particle dose (FPD) (particles <4.7 µm). However in Tables 1 and 2 fine particle mass is reported. Were these terms being used interchangeably or do the tables represent an alternative size grouping? The grouped stage data in Tables 1 and 2 suggest the FPD for test and reference are similar, but stages 6–7 show appreciable differences. The T : R ratios for SM and FP for the pMDI alone were 6.2 and 1.7, respectively, and similar with the spacer (5.2 and 1.8 for SM and FP, respectively). The testing flow rate is omitted. However if a typical flow rate of 28 l min−1 is assumed [6] then stages 6–7 would represent material with an aerodynamic particle size range of 0.4–1.1 µm[7]. Therefore, although the Andersen Cascade impactor is essentially a quality control tool and not predictive of pulmonary deposition, the test product does appear to have more finer particles, which might lead to greater peripheral lung delivery and account for the higher systemic exposure for SM reported. This difference might be related to the observed differences in stages 6–7 or be indicative of differences in distribution within the stage 3–5 grouping (1.1–4.7 µm[7]). This could be better evaluated by assessment of individual stage data. In describing clinical study 1, no details were given of the charcoal block procedure or its validation. The higher systemic exposure for SM for the generic inhaler could be interpreted as either greater lung deposition and/or altered lung deposition favouring peripheral deposition and increased systemic absorption. However, the impact of this on topical efficacy was not investigated. The design of clinical study 2 was not complimentary to study 1 as a spacer was used to administer the doses. Stopping PK sampling after 2 h was inadequate for FP, a drug with an 8 h half-life. For both drugs the impact on the primary endpoints of multiple inhalations (2–4 times the clinical dose) being given via a spacer was ignored. The time taken to administer the doses could have influenced the Cmax and tmax values observed. In the case of FP it is not clear if actual Cmax was achieved as the median value (2 h) was the last sampling point for all treatments. The reported Cmax and tmax values were therefore likely a function of the sampling schedule and time taken to administer the multiple inhalations via a spacer thereby limiting the ability to detect differences between the two inhalers. Systemic PK data are considered useful to evaluate the safety profiles of test and reference products [8], but there is doubt about their relevance as a surrogate of topical efficacy in the airways [9]. The PK data collected in these studies [1] were incomplete and the pharmacodynamic endpoints insufficiently sensitive to detect differences between the two products after a single dose. Overall, the products cannot be regarded as bioequivalent as the SM component of the test product gave higher systemic exposure. The authors’ comment that ‘pharmacokinetic analysis of plasma FP concentrations may not adequately account for the overall bioavailability of the drug, especially if the drug being examined partitions preferably into fat . . . .’ is not a relevant argument, since the test and reference products contain the same active drug moiety. Hence tissue partitioning will be the same for both products and have no influence on the outcome. On the other hand, pharmacodynamic endpoints such as overnight urinary cortisol are variable, lack sensitivity due to their non-linear relationship with drug exposure and are not sufficiently quantitative. The authors’ conclusions, that despite the PK differences, the results ‘demonstrate that generic and innovator HFA formulations of FP/SM are clinically interchangeable’ are not robust since no efficacy or safety data were presented to support their claim. There were also differences in heart rate and potassium related to the higher SM exposure from the Neolab inhaler. Therefore, in the light of the lack of PK bioequivalence for SM it cannot be argued that these differences are not clinically relevant since they are only biomarkers of systemic exposure and do not constitute an adequate assessment of the risk benefit ratio for the generic inhaler. The authors’ final conclusion that ‘a product which does not demonstrate bioequivalence in pharmacokinetic studies may still be acceptable to patients and clinicians. . . .’ is not in keeping with the accepted bioequivalence criteria. If two products are not PK equivalent then at the very least they do not have the same rate and extent of drug availability at the site of action or potentially the same systemic safety profile and therefore there is no justification for claiming bioequivalence irrespective of the route of administration or site of action. The authors are employees of GlaxoSmithKline.
Bisphosphonates are clinically useful for the treatment of bone disorders; however, there is some controversy concerning the extent to which the design of the dosage regimen influences the efficacy of these drugs. The effect of different rates of infusion of [14C] pamidronate (APD; 3-amino-1-hydroxy-propylidene-1,1-bisphosphonate) (1 mg/kg infused over 4 or 24 hr) on its pharmacokinetics was investigated in rats by the measurement of tissue disposition and plasma clearance. The pharmacokinetic parameters, including total clearance, renal clearance, and nonrenal clearance, were found to be not significantly affected by the rate of infusion. The concentration of pamidronate in tibia, liver, kidney, and spleen was also unaffected by the two infusion rates. The bone (tibia) contained the highest concentration of all the tissues sampled, and the kidney accumulated the highest concentration among the soft tissues measured; this was in contrast to previous bolus administration studies where the liver and spleen contained higher concentrations than the kidney. The disposition kinetics of pamidronate were found to be essentially multiphasic, with a rapid initial half-life that gradually tails into a very long terminal phase. A terminal half-life could not be reliably estimated as it increased with time. As a consequence a model-independent approach, based on the calculation of the total, renal, and nonrenal clearance, best served to describe the disposition kinetics of pamidronate. For this unmetabolized compound the nonrenal clearance can be ascribed to tissue binding, which appears to be essentially irreversible.(ABSTRACT TRUNCATED AT 250 WORDS)
The aim of this study was toidentify dose-related systemic effects of inhaled glucocorticoids (GCs) on the global metabolome.Metabolomics/lipidomic analysis from plasma was obtained from 54 subjects receiving weekly escalating doses (µg/day) of fluticasone furoate (FF; 25, 100, 200, 400 and 800), fluticasone propionate (FP; 50, 200, 500, 1000 and 2000), budesonide (BUD; 100, 400, 800, 1600 and 3200) or placebo. Samples (pre- and post-dose) were analysed using ultrahigh-performance liquid chromatography-tandem mass spectroscopy and liquid chromatography-mass spectrometry. Ions were matched to library standards for identification and quantification. Statistical analysis involved repeated measures ANOVA, cross-over model, random forest and principal component analysis using log-transformed data.Quantifiable metabolites (1971) had few significant changes (% increases/decreases; P < 0.05) vs placebo: FF 1.34 (0.42/0.92), FP 1.95 (0.41/1.54) and BUD 2.05 (0.60/1.45). Therapeutic doses had fewer changes: FF 0.96 (0.36/0.61), FP 1.66 (0.44/1.22) and BUD 1.45 (0.56/0.90). At highest/supratherapeutic doses, changes were qualitatively similar: reduced adrenal steroids, particularly glucuronide metabolites of cortisol and cortisone and pregnenolone metabolite DHEA-S; increased amino acids and glycolytic intermediates; decreased fatty acid β-oxidation and branched-chain amino acids. Notable qualitative differences were lowered dopamine metabolites (BUD) and secondary bile acid profiles (BUD/FF), suggesting CNS and gut microbiome effects.Dose-dependent metabolomic changes occurred with inhaled GCs but were seen predominately at highest/supratherapeutic doses, supporting the safety of low and mid therapeutic doses. At comparable therapeutic doses (FF 100, FP 500 and BUD 800 µg/day), FF had the least effect on the most sensitive markers (adrenal steroids) vs BUD and FP.
Summary We report the results of two consecutive randomized studies in the treatment of malignant hypercalcaemia with intravenous pamidronate. Overall normocalcaemia was achieved in greater than 90% of patients and a single infusion of 60 mg pamidronate given over 2 hours was as effective in restoring normocalcaemia as infusions given over 4, 8 or 24 hours. Similarly duration of normocalcemia after treatment with pamidronate and the control of the symptoms of hypercalcaemia were independent of infusion rate. Study of the pharmacokinetics of pamidronate in the treatment of hypercalcaemia show this drug to have a very high clearance due to calcified tissue retention and renal excretion. The initial half life of the drug in plasma is very short and most of the drug is cleared before distribution equilibrium is achieved. Short infusions of pamidronate are as safe and effective as infusions given over a longer time and are therefore to be preferred because of their greater convenience.
The degree of systemic exposure ofter inhalation of corticosteroids is of great clinical concern. For optimum outcome, the pulmonary deposition should be sufficiently high to produce the desired anti-inflammatory effect in the lungs, whereas the plasma concentrations due to the absorption of the corticosteroid from the lung and the gut should be minimal. Recently, it has been reported that inhaled mometasone furoate has a systemic bioavailability of less than 1%, which is much lower than other corticosteroids currently available. However, critical evaluation of the study methodology and results does not support this finding. A major shortfall of the study was an insufficient analytical sensitivity, resulting in a calculated average plasma concentration profile that was entirely below the limit of quantification. These numbers were generated by replacing all concentrations below the limit of quantification byzero and then calculating an average value. This procedure can lead to erroneous results and misinterpretation. Furthermore, the potential contribution of active metabolites needs to be adequately addressed in comparisons of inhaled corticosteroids. Reliable estimates of systemic drug exposure are critical in evaluating the real safety profiles and therapeutic index for inhaled corticosteroids that are effective in treating chronic asthma.
To the Editors:
Recently, the systemic bioavailability of mometasone furoate (MF) via the TwisthalerTM (Schering Corp., Kenilworth, NJ, USA) has been reported to be <1% in healthy subjects 1. This unusual result, however, was based on a study with sparse data, a low dose ( i.e . 400 µg) and a relatively insensitive assay (lower limit of detection of 50 pg·mL−1). Plasma concentrations were said to be undetectable in 10 of the 24 subjects in whom this assay was used.
The absolute systemic bioavailability for an inhaled drug is calculated by comparing the area under the plasma concentration-time curve for inhaled dosing, with that obtained following intravenous dosing. To obtain a reliable estimate, the administered doses need to be large enough to produce measurable plasma concentrations. Therefore, an estimate of the true systemic bioavailability of MF cannot reliably be made based on incomplete data and an insensitive assay, and certainly not compared with …
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