Physiologically based modelling of tranexamic acid pharmacokinetics following intravenous, intramuscular, sub-cutaneous and oral administration in healthy volunteers.

BACKGROUND: Tranexamic acid (TXA) is an antifibrinolytic drug that reduces surgical blood loss and death due to bleeding after trauma and post-partum haemorrhage. Treatment success is dependant on early intervention and rapid systemic exposure to TXA. The requirement for intravenous (IV) administration can in some situations limit accessibility to TXA therapy. Here we employ physiologically based pharmacokinetic modelling (PBPK) to evaluate if adequate TXA exposure maybe achieved when given via different routes of administration. METHODS: A commercially available PBPK software (GastroPlus®) was used to model published TXA pharmacokinetics. IV, oral and intramuscular (IM) models were developed using healthy volunteer PK data from twelve different single dose regimens (n = 48 participants). The model was verified using separate IV and oral validation datasets (n = 26 participants). Oral, IM and sub-cutaneous (SQ) dose finding simulations were performed. RESULTS: Across the different TXA regimens evaluated TXA plasma concentrations varied from 0.1 to 94.0 µg/mL. Estimates of the total plasma clearance of TXA ranged from 0.091 to 0.104 L/h/kg, oral bioavailability from 36 to 67% and Tmax from 2.6 to 3.2 and 0.4 to 1.0 h following oral and intramuscular administration respectively. Variability in the observed TXA PK could be captured through predictable demographic effects on clearance, combined with intestinal permeability and stomach transit time following oral administration and muscle blood flow and muscle/plasma partition coefficients following intra-muscular dosing. CONCLUSIONS: This study indicates that intramuscular administration is the non-intravenous route of administration with the most potential for achieving targeted TXA exposures. Plasma levels following an IM dose of 1000 mg TXA are predicted to exceed 15 mg/mL in < 15 min and be maintained above this level for approximately 3 h, achieving systemic exposure (AUC0-6) of 99 to 105 µg*hr/mL after a single dose. Well-designed clinical trials to verify these predictions and confirm the utility of intramuscular TXA are recommended.

Evaluating the Introduction of an Allied Health Clinical Research Office at a Health Service: Effects on Research Participation, Interest, and Experience of Allied Health Professionals.

Following the introduction of an allied health clinical research office at a large metropolitan health service, we aimed to measure change in self-reported research participation, interest and experience of allied health professionals. METHODS: Allied health professionals were surveyed using the Research Spider tool in 2015 (n=245), and the results were compared to a similar survey completed in 2007 at the same health service (n=132). RESULTS: Overall, allied health professionals rated themselves as having "some research interest" and "little research experience," with no significant difference from 2007 to 2015. Allied health professionals with at least some research interest reported increased experience in critically reviewing literature (p=0.045) and finding relevant literature (p=0.009) and a trend to increased experience of publishing research (p=0.059) in 2015 compared with 2007. The proportion of allied health professionals who classified themselves as participating in research had increased from 41% in 2007 to 51% in 2015 (p=0.028). CONCLUSIONS: The introduction of an allied health clinical research office has been associated with increased participation in research with some improvements in research experience for those with at least some interest in research. Despite these positive changes, most allied health professionals at this health service still report little research experience and only some interest in research.

Hepatic uptake in the dog: comparison of uptake in hepatocytes and human embryonic kidney cells expressing dog organic anion-transporting polypeptide 1B4.

Although the dog is frequently used in pharmacological, pharmacokinetic, and drug safety studies, little is known about canine drug transporters. Dog organic anion-transporting polypeptide (Oatp1b4) has recently been cloned (Comp Biochem Physiol C Toxicol Pharmacol 151:393-399, 2010), but the contribution of Oatp1b4 to hepatic uptake has yet to be clarified. This study compares the transport characteristics of dog Oatp1b4 with those of human OATP1B1/1B3 and demonstrates the importance of Oatp1b4 in the uptake of anionic compounds in dog hepatocytes. Oatp1b4 is the predominant Oatp in dog liver with expression levels double and 30 times those of Oatp2b1 and Oatp1a2, respectively. Uptake of a range of typical OATP substrates by Oatp1b4-expressing HEK293 cells was compared with that in fresh dog hepatocytes. All compounds tested were transported by Oatp1b4 and uptake intrinsic clearance (CL(int, uptake)) in dog hepatocytes in sodium-free buffer was correlated significantly with CL(int, uptake) in Oatp1b4-expressing cells. Dog in vivo clearance for five substrates was predicted more accurately from CL(int, uptake) than from metabolic intrinsic clearance (CL(int, met)), indicating that uptake governs the overall in vivo hepatic clearance of these anionic compounds in dog. The substrate specificities of dog Oatp1b4 appear to be similar to those of human OATP1B1/OATP1B3, whereas the relative uptake clearance of substrates for Oatp1b4 correlate better with OATP1B3 than with the more abundant hepatic analog OATP1B1.

Development and evaluation of an allied health research training scheme.

Allied health professionals are increasingly encouraged to utilise clinical research skills within their practice. While undergraduate allied health courses include some training in basic research skills, little is known about the most effective methods of continuing research training into professional life. This paper describes the implementation and evaluation of a 12-week allied health research training program, targeting interested clinicians and utilising a mixed approach of group learning and individual mentoring to guide participants through the process of conducting a systematic review of the literature. Evaluation included a qualitative analysis of in-depth semi-structured interviews with the first cohort of participants who completed the program (n=6) and their mentors (n=6), a quantitative analysis of changes in research interest, experience, and confidence of those who enrolled in the program (n=7) using the Research Spider tool, and a 6-month follow-up of research outputs resulting from the program. Results indicated that the program was beneficial, although the time and new learning required was a challenge for both participants and mentors. A significant increase was observed in research confidence, as well as an observed improvement in research experience, that approached but did not achieve statistical significance (p=0.06). At 6-month follow-up, the program had led to the submission of three papers for publication and one conference presentation. The results of the evaluation indicate that a research training program targeting motivated and interested clinicians and utilising existing resources can lead to tangible outputs within a clinical setting.

Comparative use of isolated hepatocytes and hepatic microsomes for cytochrome P450 inhibition studies: transporter-enzyme interplay.

Accurate assignment of the concentration of victim drug/inhibitor available at the enzyme active site, both in vivo and within an in vitro incubation, is an essential requirement in rationalizing and predicting drug-drug interactions. Inhibitor accumulation within the liver, whether as a result of active transport processes or intracellular binding, may best be accounted for using hepatocytes rather than hepatic microsomes to estimate in vitro inhibitory potency. The aims of this study were to compare K(i) values determined in rat liver microsomes and freshly isolated rat hepatocytes of four cytochrome P450 (P450) inhibitors (clarithromycin, enoxacin, nelfinavir, and saquinavir) with known hepatic transporter involvement and a range of uptake (cell/medium concentration ratios 20-3000) and clearance (10-1200 µl/min/10(6) cells) properties. Inhibition studies were performed using two well established P450 probe substrates (theophylline and midazolam). Comparison of unbound K(i) values showed marked differences between the two in vitro systems for inhibition of metabolism. In two cases (clarithromycin and enoxacin, both low-clearance drugs), inhibitory potency in hepatocytes markedly exceeded that in microsomes (10- to 20-fold), and this result was consistent with their high cell/medium concentration ratios. For nelfinavir and saquinavir (high-clearance, extensively metabolized drugs), the opposite trend was seen in the K(i) values: despite very high cell/medium concentration ratios, stronger inhibition was evident within microsomal preparations. Hence, the consequences of hepatic accumulation resulting from uptake transporters vary according to the clearance of the inhibitor. This study demonstrates that transporter-enzyme interplay can result in differences in inhibitory potency between microsomes and hepatocytes and hence drug-drug interaction predictions that are not always intuitive.