Safety, pharmacokinetics, and pharmacodynamics of intravenous ferric carboxymaltose in children with iron deficiency anemia.

BACKGROUND: Iron deficiency is the primary cause of anemia in children. Intravenous (IV) iron formulations circumvent malabsorption and rapidly restore hemoglobin. METHODS: This Phase 2, non-randomized, multicenter study characterized the safety profile and determined appropriate dosing of ferric carboxymaltose (FCM) in children with iron deficiency anemia. Patients aged 1-17 years with hemoglobin <11 g/dL and transferrin saturation <20% received single IV doses of undiluted FCM 7.5 mg/kg (n = 16) or 15 mg/kg (n = 19). RESULTS: The most common drug-related treatment-emergent adverse event was urticaria (in three recipients of FCM 15 mg/kg). Systemic exposure to iron increased in a dose-proportional manner with approximate doubling of mean baseline-corrected maximum serum iron concentration (157 µg/mL with FCM 7.5 mg/kg; and 310 µg/mL with FCM 15 mg/kg) and area under the serum concentration-time curve (1901 and 4851 h·µg/mL, respectively). Baseline hemoglobin was 9.2 and 9.5 g/dL in the FCM 7.5 and 15 mg/kg groups, respectively, with mean maximum changes in hemoglobin of 2.2 and 3.0 g/dL, respectively. CONCLUSIONS: In conclusion, FCM was well tolerated by pediatric patients. Improvements in hemoglobin were greater with the higher dose, supporting use of the FCM 15 mg/kg dose in pediatric patients (Clinicaltrials.gov NCT02410213). IMPACT: This study provided information on the pharmacokinetics and safety of intravenous ferric carboxymaltose for treatment of iron deficiency anemia in children and adolescents. In children aged 1-17 years with iron deficiency anemia, single intravenous doses of ferric carboxymaltose 7.5 or 15 mg/kg increased systemic exposure to iron in a dose-proportional manner, with clinically meaningful increases in hemoglobin. The most common drug-related treatment-emergent adverse event was urticaria. The findings suggest that iron deficiency anemia in children can be corrected with a single intravenous dose of ferric carboxymaltose and support use of a 15 mg/kg dose.

Tissue lipids and drug distribution: dog versus rat.

A key parameter in whole-body physiologically based pharmacokinetic models is the tissue-to-plasma water partition coefficient (K(pu)), which is commonly assumed consistent across all species for all tissues for passively distributing drugs. Many drugs primarily bind to tissue lipids and although considerable tissue lipid concentration data exist in rodents, data on these and K(pu) values in larger animals and humans are sparse to negligible. To test the above assumption, lipid levels were quantified in 13 dog tissues, then compared with the values in rat, and used to predict and compare K(pu) values between these species. For many tissues, including muscle, lipid concentrations were comparable in dog and rat. However, spleen acidic phospholipid levels were sevenfold lower, skin neutral phospholipid threefold lower, and neutral lipids fivefold, 12-fold, and eightfold lower in brain, lung, and spleen, respectively, and fourfold higher in bone in dog than in rat. Such differences resulted in significant predicted K(pu) differences. In contrast, unbound volume of distribution (Vu(ss)), a global measure of distribution, showed generally good agreement (predictions and observations) between dog and rat for a diverse compound set, indicating tissues with large-predicted K(pu) species differences tend either to contribute to Vu(ss) to a limited extent, and/or occur in opposing directions tending to cancel each other out.

Mechanistic approaches to volume of distribution predictions: understanding the processes.

PURPOSE: To use recently developed mechanistic equations to predict tissue-to-plasma water partition coefficients (Kpus), apply these predictions to whole body unbound volume of distribution at steady state (Vu(ss)) determinations, and explain the differences in the extent of drug distribution both within and across the various compound classes. MATERIALS AND METHODS: Vu(ss) values were predicted for 92 structurally diverse compounds in rats and 140 in humans by two approaches. The first approach incorporated Kpu values predicted for 13 tissues whereas the second was restricted to muscle. RESULTS: The prediction accuracy was good for both approaches in rats and humans, with 64-78% and 82-92% of the predicted Vu(ss) values agreeing with in vivo data to within factors of +/-2 and 3, respectively. CONCLUSIONS: Generic distribution processes were identified as lipid partitioning and dissolution where the former is higher for lipophilic unionised drugs. In addition, electrostatic interactions with acidic phospholipids can predominate for ionised bases when affinities (reflected by binding to constituents within blood) are high. For acidic drugs albumin binding dominates when plasma protein binding is high. This ability to explain drug distribution and link it to physicochemical properties can help guide the compound selection process.

Physiologically based pharmacokinetic modelling 2: predicting the tissue distribution of acids, very weak bases, neutrals and zwitterions.

A key component of whole body physiologically based pharmacokinetic (WBPBPK) models is the tissue-to-plasma water partition coefficients (Kpu's). The predictability of Kpu values using mechanistically derived equations has been investigated for 7 very weak bases, 20 acids, 4 neutral drugs and 8 zwitterions in rat adipose, bone, brain, gut, heart, kidney, liver, lung, muscle, pancreas, skin, spleen and thymus. These equations incorporate expressions for dissolution in tissue water and, partitioning into neutral lipids and neutral phospholipids. Additionally, associations with acidic phospholipids were incorporated for zwitterions with a highly basic functionality, or extracellular proteins for the other compound classes. The affinity for these cellular constituents was determined from blood cell data or plasma protein binding, respectively. These equations assume drugs are passively distributed and that processes are nonsaturating. Resultant Kpu predictions were more accurate when compared to published equations, with 84% as opposed to 61% of the predicted values agreeing with experimental values to within a factor of 3. This improvement was largely due to the incorporation of distribution processes related to drug ionisation, an issue that is not addressed in earlier equations. Such advancements in parameter prediction will assist WBPBPK modelling, where time, cost and labour requirements greatly deter its application.

Optimal design for multivariate response pharmacokinetic models.

We address the problem of designing pharmacokinetic experiments in multivariate response situations. Criteria, based on the Fisher information matrix, whose inverse according to the Rao-Cramer inequality is the lower bound of the variance-covariance matrix of any unbiased estimator of the parameters, have previously been developed for univariate response for an individual and a population. We extend these criteria to design individual and population studies where more than one response is measured, for example, when both parent drug and metabolites are measured in plasma, multi-compartment models, where measurements are taken at more than one site, or when drug concentration and pharmacodynamic data are collected simultaneously. We assume that measurements made at distinct times are independent, but measurements made of each concentration are correlated with a response variance-covariance matrix. We investigated a number of optimisation algorithms, namely simplex, exchange, adaptive random search, simulated annealing and a hybrid, to maximise the determinant of the Fisher information matrix as required by the D-optimality criterion. The multiresponse optimal design methodology developed was applied in two case studies, where the aim was to suggest optimal sampling times. The first was a restrospective iv infusion experiment aimed to characterise the disposition kinetics of tolcapone and its two metabolites in healthy volunteers. The second was a prospective iv bolus experiment designed to estimate the tissue disposition kinetics of eight beta-blockers in rat.

Tissue distribution of basic drugs: accounting for enantiomeric, compound and regional differences amongst beta-blocking drugs in rat.

The purpose of this research was to identify the major factors controlling the distribution of beta-blockers (acebutolol, betaxolol, bisoprolol, metoprolol, oxprenolol, pindolol, propranolol and timolol) in rats, across tissues, compounds and enantiomers. Tissue distribution was assessed at steady state by infusing cassette doses of beta-blockers into the jugular vein via an indwelling catheter at a constant rate. Blood was sampled via an indwelling catheter in the carotid artery, and 12 tissues excised at the end of dose infusion (4 or 8 h). Drug concentrations were quantified using a novel chiral LC-MS method and the tissue-to-plasma (Kp) and tissue-to-plasma water (Kpu) values were calculated for each tissue. Differences between Kp were observed between many enantiomeric pairs, and largely explained by enantiomeric differences in plasma protein binding. Across compounds, Kpu values were generally highest in lung and lowest in adipose, and were higher for the more lipophilic drugs betaxolol and propranolol. For any tissue, Kpu differences between the individual beta-blockers correlated well with the corresponding affinity for blood cells. For all compounds, regional tissue distribution correlated well with tissue acidic phospholipid concentrations, with phosphatidylserine appearing to have the strongest influence. This information may be used as the basis for predicting the tissue distribution of basic drugs.

Physiologically based pharmacokinetic modeling 1: predicting the tissue distribution of moderate-to-strong bases.

Tissue-to-plasma water partition coefficients (Kpu's) form an integral part of whole body physiologically based pharmacokinetic (WBPBPK) models. This research aims to improve the predictability of Kpu values for moderate-to-strong bases (pK(a) > or = 7), by developing a mechanistic equation that accommodates the unique electrostatic interactions of such drugs with tissue acidic phospholipids, where the affinity of this interaction is readily estimated from drug blood cell binding data. Additional model constituents are drug partitioning into neutral lipids and neutral phospholipids, and drug dissolution in tissue water. Major assumptions of this equation are that electrostatic interactions predominate, drugs distribute passively, and non-saturating conditions prevail. Resultant Kpu predictions for 28 moderate-to-strong bases were significantly more accurate than published equations with 89%, compared to 45%, of the predictions being within a factor of three of experimental values in rat adipose, bone, gut, heart, kidney, liver, muscle, pancreas, skin, spleen and thymus. Predictions in rat brain and lung were less accurate probably due to the involvement of additional processes not incorporated within the equation. This overall improvement in prediction should facilitate the further application of WBPBPK modeling, where time, cost and labor requirements associated with experimentally determining Kpu's have, to a large extent, deterred its application.