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BackgroundThis study aimed to assess the pediatric lisinopril doses using an adult physiological based pharmacokinetic (PBPK) model. As the empirical rules of dose calculation cannot calculate gender-specific pediatric doses and ignores the age-related physiological differences.MethodsA PBPK model of lisinopril for the healthy adult population was developed for oral (fed and fasting) and IV administration using PK-Sim MoBI® and was scaled down to a virtual pediatric population for prediction of lisinopril doses in neonates to infants, infants to toddler, children at pre-school age, children at school age and the adolescents. The pharmacokinetic parameters were predicted for the above groups at decremental doses of 20 mg, 10 mg, 5 mg, 2.5 mg, and 1.5 mg in order to accomplish doses producing the pharmacokinetic parameters, similar (or comparable) to that of the adult population. The above simulated pediatric doses were compared to the doses computed using the conventional four methods, such as Young’s rule, Clark’s rule, and weight-based and body surface area-based equations and the dose reported in different studies.ResultsThough the doses predicted for all subpopulations of children were comparable to those calculated by Young’s rule, yet the conventional methods overestimated the pediatric doses when compared to the respective PBPK-predicted doses. The findings of previous real time pharmacokinetic studies in pediatric patients supported the present simulated dose.ConclusionThus, PBPK seems to have predictability potential for pediatric dose since it takes into consideration the physiological changes related to age and gender.

Background and purpose Human pharmacokinetic studies of lung-targeted drugs are typically limited to measurements of systemic plasma concentrations, which provide no direct information on lung target-site concentrations. We aimed to evaluate lung pharmacokinetics of commonly prescribed drugs by sampling different lung compartments after inhalation and oral administration. Experimental approach Healthy volunteers received single, sequential doses of either inhaled salbutamol, salmeterol, and fluticasone propionate (n=12), or oral salbutamol and propranolol (n=6). Each participant underwent bronchoscopies and gave breath samples for analysis of particles in exhaled air at two time points after drug administration (1 and 6, 2 and 9, 3 and 12, or 4 and 18 hours). Lung samples were taken via bronchosorption, bronchial brush, mucosal biopsy, and bronchoalveolar lavage during each bronchoscopy. Blood samples were taken during the 24 hours after administration. Pharmacokinetic profiles were generated by combining data from multiple individuals, covering all sample timings. Key results Pharmacokinetic profiles were obtained for each drug in lung epithelial lining fluid, lung tissue, and plasma. Inhalation of salbutamol resulted in approximately 100-fold higher concentrations in lung versus plasma. Salmeterol and fluticasone concentration ratios in lung versus plasma were higher still. Bronchosorption- and bronchoalveolar-lavage-generated profiles of inhaled drugs in epithelial lining fluid were comparable, whereas, for oral drugs, epithelial-lining-fluid concentrations appeared to be overestimated in bronchoalveolar-lavage-generated profiles. Conclusion and implications Combining pharmacokinetic data derived from multiple individuals and techniques sampling different lung compartments enabled generation of pharmacokinetic profiles for evaluation of lung targeting after inhaled and oral drug delivery.

Aims This 3-part, randomised, phase 1 first-in-human study (NCT03436316) investigated the safety, tolerability and pharmacokinetics (PK) of AZD8154, a dual phosphoinositide 3-kinase (PI3K) γδ inhibitor developed as a novel inhaled anti-inflammatory treatment for respiratory disease. Methods Healthy men, and women of nonchildbearing potential, were enrolled to receive single and multiple ascending inhaled doses of AZD8154 in parts 1 and 3 of the study, respectively, while part 2 characterised the systemic PK after a single intravenous (IV) dose. In part 1, participants received 0.1-7.7 mg AZD8154 in 6 cohorts. In part 2, participants were given 0.15 mg AZD8154 as an IV infusion. In part 3, AZD8154 was given in 3 cohorts of 0.6, 1.8 and 3.1 mg, with a single dose on Day 1 followed by repeated once-daily doses on Days 4-12. Results In total, 78 volunteers were randomised. All single inhaled, single IV and multiple inhaled doses were shown to be well tolerated without any safety concerns. A population PK model, using nonlinear mixed-effect modelling, was developed to describe the PK of AZD8154. The terminal mean half-life of AZD8154 was 18.0-32.0 hours. The geometric mean of the absolute pulmonary bioavailability of AZD8154 via the inhaled route was 94.1%. Conclusion AZD8154 demonstrated an acceptable safety profile, with no reports of serious adverse events and no clinically significant drug-associated safety concerns reported in healthy volunteers. AZD8154 demonstrated prolonged lung retention and a half-life supporting once-daily dosing.

After inhaled drug administration, pharmacokinetic (PK) data is typically limited to plasma concentrations and provides no direct information on lung target site levels. This study aims to increase understanding of regional lung PK of selected drugs by taking samples from various lung compartments using innovative sampling methods. Eighteen healthy volunteers were enrolled to either receive single doses of orally inhaled salbutamol (200µg), salmeterol (50µg) and fluticasone propionate (500µg) (n=12) or single oral doses of salbutamol (4 mg) and propranolol (40 mg) (n=6). Two bronchoscopies were performed in each subject. During each bronchoscopy 2 samples of bronchosorption, bronchial brush, mucosal biopsy and one bronchoalveolar lavage (BAL) were performed at different pre-specified times (1, 2, 3, 4, 6, 9, 12, 18 hours) after the drug administration. PK profiles of the model drugs were obtained for concentrations in human lung epithelial lining fluid and lung tissue, enabling insight into the spatial lung distribution of drugs after inhaled and oral administration (Fig. 1). Innovative study design with direct sampling from different compartments in lung provided high quality PK profiles in human lung and demonstrated extent of lung targeting following inhaled drug delivery.

AZD8154 is an inhaled PI3Kgd inhibitor developed for treatment of asthma. This first in human study evaluate the safety, tolerability and PK of AZD8154 in healthy volunteers after inhalation of single ascending doses (Part 1) and characterized the systemic PK after an intravenous (IV) dose (Part 2). This was a randomized, single-blind, placebo-controlled and sequential group design study. In Part 1, subjects received AZD8154 target delivered doses of 0.1, 0.3, 0.9, 2.7, 5.4 and 7.7 mg via nebulisation respectively in six cohorts (6:2 active:placebo). In Part 2, 0.15 mg AZD8154 was administered IV to six subjects, after a wash-out period they were given 2.7 mg inhaled target delivered dose. Overall, single inhaled doses of AZD8154 up to target delivered dose 7.7 mg were well tolerated and no safety concerns were raised. A population PK model, using non-linear mixed effect modelling, was developed to describe the PK of AZD8154. The final PK model successfully described the trends and variability in the data. The PK of AZD8154 was characterized by an early rapid absorption phase with tmax occurring at 0.17 to 0.75 h, followed by a flat period of about 12 - 24 h, before declining in a typically mono-phasic manner. The systemic exposure of AZD8154 increased in a dose proportional manner. The terminal mean half-life was 18 to 29 h and the pulmonary bioavailability was on average 94%. In summary, AZD8154 displayed dose proportional PK characteristics in the dose range studied (0.1 to 7.7 mg) with a half-life potentially suitable for once-daily dosing and the data supports further evaluation in a multiple ascending dose study.

The purpose of this study was to develop a whole-body physiologically based pharmacokinetic (WB-PBPK) model for ciprofloxacin for ICU patients, based on only plasma concentration data. In a next step, tissue and organ concentration time profiles in patients were predicted using the developed model. The WB-PBPK model was built using a non-linear mixed effects approach based on data from 102 adult intensive care unit patients. Tissue to plasma distribution coefficients (Kp) were available from the literature and used as informative priors. The developed WB-PBPK model successfully characterized both the typical trends and variability of the available ciprofloxacin plasma concentration data. The WB-PBPK model was thereafter combined with a pharmacokinetic–pharmacodynamic (PKPD) model, developed based on in vitro time-kill data of ciprofloxacin and Escherichia coli to illustrate the potential of this type of approach to predict the time-course of bacterial killing at different sites of infection. The predicted unbound concentration–time profile in extracellular tissue was driving the bacterial killing in the PKPD model and the rate and extent of take-over of mutant bacteria in different tissues were explored. The bacterial killing was predicted to be most efficient in lung and kidney, which correspond well to ciprofloxacin’s indications pneumonia and urinary tract infections. Furthermore, a function based on available information on bacterial killing by the immune system in vivo was incorporated. This work demonstrates the development and application of a WB-PBPK–PD model to compare killing of bacteria with different antibiotic susceptibility, of value for drug development and the optimal use of antibiotics . Electronic supplementary material The online version of this article (doi:10.1007/s10928-016-9486-9) contains supplementary material, which is available to authorized users.

Morphine has been predicted to show nonlinear blood-brain barrier transport at lower concentrations. In this study, we investigated the possibility of separating active influx of morphine from its efflux by using very low morphine concentrations and compared accelerator mass spectrometry (AMS) with liquid chromatography-tandem mass spectrometry (LC-MS/MS) as a method for analyzing microdialysis samples. A 10-min bolus infusion of morphine, followed by a constant-rate infusion, was given to male rats (n = 6) to achieve high (250 ng/ml), medium (50 ng/ml), and low (10 ng/ml) steady-state plasma concentrations. An additional rat received infusions to achieve low (10 ng/ml), very low (2 ng/ml), and ultralow (0.4 ng/ml) concentrations. Unbound morphine concentrations from brain extracellular fluid and blood were sampled by microdialysis and analyzed by LC-MS/MS and AMS. The average partition coefficient for unbound drug (K(p,uu)) values for the low and medium steady-state levels were 0.22 ± 0.08 and 0.21 ± 0.05, respectively, when measured by AMS [not significant (NS); p = 0.5]. For the medium and high steady-state levels, K(p,uu) values were 0.24 ± 0.05 and 0.26 ± 0.05, respectively, when measured by LC-MS/MS (NS; p = 0.2). For the low, very low, and ultralow steady-state levels, K(p,uu) values were 0.16 ± 0.01, 0.16 ± 0.02, and 0.18 ± 0.03, respectively, when measured by AMS. The medium-concentration K(p,uu) values were, on average, 16% lower when measured by AMS than by LC-MS/MS. There were no significant changes in K(p,uu) over a 625-fold concentration range (0.4-250 ng/ml). It was not possible to separate active uptake transport from active efflux using these low concentrations. The two analytical methods provided indistinguishable results for plasma concentrations but differed by up to 38% for microdialysis samples; however, this difference did not affect our conclusions.

Diphenhydramine (DPHM) and oxycodone are weak bases that are able to form cations. Both drugs show active uptake at the blood-brain barrier (BBB). There is thus a possibility for a pharmacokinetic interaction between them by competition for the same uptake transport system. The experiments of the present study were designed to study the transport of DPHM across the BBB and its interaction with oxycodone in vitro and in vivo. In vitro ,t he interaction between the drugs was studied using conditionally immortalized rat brain capillary endothelial cells (TR-BBB13 cells). The in vivo relevance of the in vitro findings was studied in rats using brain and blood microdialysis. DPHM was actively transported across the BBB in vitro (TR-BBB13 cells). Oxycodone competitively inhibited DPHM uptake with a Ki value of 106 :M. DPHM also competitively inhibited oxycodone uptake with a Ki value of 34.7 :M. In rats, DPHM showed fivefold higher unbound concentration in brain interstitial fluid (ISF) than in blood, confirming a net active uptake. There was no significant interaction between DPHM and oxycodone in vivo. This accords with the results of the in vitro experiments because the unbound plasma concentrations that could be attained in vivo, without causing adverse effects, were far below the Ki values. © 2011 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:3912-3923, 2011