Translational learning from clinical studies predicts drug pharmacokinetics across patient populations.

Early indication of late-stage failure of novel candidate drugs could be facilitated by continuous integration, assessment, and transfer of knowledge acquired along pharmaceutical development programs. We here present a translational systems pharmacology workflow that combines drug cocktail probing in a specifically designed clinical study, physiologically based pharmacokinetic modeling, and Bayesian statistics to identify and transfer (patho-)physiological and drug-specific knowledge across distinct patient populations. Our work builds on two clinical investigations, one with 103 healthy volunteers and one with 79 diseased patients from which we systematically derived physiological information from pharmacokinetic data for a reference probe drug (midazolam) at the single-patient level. Taking into account the acquired knowledge describing (patho-)physiological alterations in the patient cohort allowed the successful prediction of the population pharmacokinetics of a second, candidate probe drug (torsemide) in the patient population. In addition, we identified significant relations of the acquired physiological processes to patient metadata from liver biopsies. The presented prototypical systems pharmacology approach is a proof of concept for model-based translation across different stages of pharmaceutical development programs. Applied consistently, it has the potential to systematically improve predictivity of pharmacokinetic simulations by incorporating the results of clinical trials and translating them to subsequent studies.

Effects of cerebral hypoperfusion on bispectral index: a randomised, controlled animal experiment during haemorrhagic shock.

BACKGROUND: The aim of this porcine haemorrhagic shock model was to investigate the changes of bispectral index (BIS) after slow and fast recovery of cerebral perfusion, and its correlation with plasma propofol concentrations. METHODS: After Animal Investigational Committee approval, 16 pigs during propofol anaesthesia underwent a liver trauma with severe hypotension, and were randomly assigned to receive therapy for either slow recovery (fluid resuscitation; slow group; n=8) or fast recovery of cerebral perfusion (vasopressor combined with hypertonic-saline-starch; fast group; n=8), respectively. Cerebral perfusion pressure (CPP=MAP-ICP), cerebral tissue oxygenation index (TOI), BIS, and plasma concentrations of propofol and haemoglobin were measured at baseline (Pre-shock), haemodynamic decompensation (Shock), and 5 (Therapy) and 30 min (End) after therapy, respectively. RESULTS: CPP, TOI, and BIS decreased significantly during shock (pre-shock vs. shock, fast: CPP: 65+/-14 vs. 15+/-4 mmHg; TOI: 64+/-6 vs. 47+/-7%; BIS 60+/-5 vs. 9+/-10; slow: CPP: 60+/-12 vs. 13+/-7 mmHg; TOI: 68+/-7 vs. 49+/-7%; BIS 63+/-5 vs. 13+/-12; P<0.05). In the fast group, CPP, TOI, and BIS increased after therapy compared to the slow group (Therapy, fast: CPP: 47+/-15 mmHg, TOI: 61+/-7%, BIS: 47+/-21; slow: CPP: 18+/-9 mmHg, TOI: 51+/-5%, BIS: 21+/-19; P<0.05). Propofol and haemoglobin concentrations were comparable between groups throughout the resuscitation phase. CONCLUSIONS: In a haemorrhagic shock scenario, therapies with different impact on cerebral perfusion resulted in differing changes of BIS values, while plasma propofol and haemoglobin concentrations were comparable during the resuscitation phase; this suggests that BIS may also have reflected changes of cerebral perfusion.

Comparison of surgical stress index-guided analgesia with standard clinical practice during routine general anesthesia: a pilot study.

BACKGROUND: Surgical stress index (SSI), a novel multivariate index, has recently been proven to react well to surgical nociceptive stimuli and analgesic drug concentration changes during general anesthesia. We investigated the feasibility of application of SSI for guidance of remifentanil administration during propofol-remifentanil anesthesia. METHODS: Eighty patients scheduled for elective ear-nose-throat surgery were randomized into two groups, SSI-guided analgesia group (SSI group) and standard practice analgesia group (control group). In both groups, anesthesia was maintained with a propofol target-controlled infusion and adjusted stepwise by 0.5 microg/ml to keep bispectral index values between 40 and 60. In the SSI group, the predicted effect-site concentration of remifentanil was adjusted stepwise by 1 ng/ml to keep SSI values between 20 and 50, whereas in the control group, predicted effect-site concentration of remifentanil was adjusted according to traditional inadequate analgesia criteria. Anesthetics consumption, recovery times, and incidence of unwanted events were recorded. RESULTS: Remifentanil consumption (average normalized infusion rate) was lower in the SSI group than in the control group (mean +/- SD, 9.5 +/- 3.8 microg . kg(-1) . h(-1) vs. 12.3 +/- 5.2 microg . kg(-1) . h(-1); P < 0.05). The number of unwanted events was less in the SSI group (84) than in the control group (556; P < 0.01). Recovery times were comparable between groups. No patient reported intraoperative recall. CONCLUSIONS: SSI-guided anesthesia resulted in lower remifentanil consumption, more stable hemodynamics, and a lower incidence of unwanted events.