From data to QSP models: a pipeline for using Boolean networks for hypothesis inference and dynamic model building.

Quantitative Systems Pharmacology (QSP) models capture the physiological underpinnings driving the response to a drug and express those in a semi-mechanistic way, often involving ordinary differential equations (ODEs). The process of developing a QSP model generally starts with the definition of a set of reasonable hypotheses that would support a mechanistic interpretation of the expected response which are used to form a network of interacting elements. This is a hypothesis-driven and knowledge-driven approach, relying on prior information about the structure of the network. However, with recent advances in our ability to generate large datasets rapidly, often in a hypothesis-neutral manner, the opportunity emerges to explore data-driven approaches to establish the network topologies and models in a robust, repeatable manner. In this paper, we explore the possibility of developing complex network representations of physiological responses to pharmaceuticals using a logic-based analysis of available data and then convert the logic relations to dynamic ODE-based models. We discuss an integrated pipeline for converting data to QSP models. This pipeline includes using k-means clustering to binarize continuous data, inferring likely network relationships using a Best-Fit Extension method to create a Boolean network, and finally converting the Boolean network to a continuous ODE model. We utilized an existing QSP model for the dual-affinity re-targeting antibody flotetuzumab to demonstrate the robustness of the process. Key output variables from the QSP model were used to generate a continuous data set for use in the pipeline. This dataset was used to reconstruct a possible model. This reconstruction had no false-positive relationships, and the output of each of the species was similar to that of the original QSP model. This demonstrates the ability to accurately infer relationships in a hypothesis-neutral manner without prior knowledge of a system using this pipeline.

A Six-Stage Workflow for Robust Application of Systems Pharmacology.

Quantitative and systems pharmacology (QSP) is increasingly being applied in pharmaceutical research and development. One factor critical to the ultimate success of QSP is the establishment of commonly accepted language, technical criteria, and workflows. We propose an integrated workflow that bridges conceptual objectives with underlying technical detail to support the execution, communication, and evaluation of QSP projects.

Bridging Sunitinib Exposure to Time-to-Tumor Progression in Hepatocellular Carcinoma Patients With Mathematical Modeling of an Angiogenic Biomarker.

Hepatocellular carcinoma (HCC) is third in cancer-related causes of death worldwide and its treatment is a significant unmet medical need. Sunitinib is a selective tyrosine kinase inhibitor of the angiogenic biomarker: soluble vascular endothelial growth factor receptor-2 (sVEGFR2 ). Sunitinib failed its primary overall survival endpoint in patients with advanced HCC in a phase III trial compared to sorafenib. In the present study, pharmacokinetic-pharmacodynamic modeling was used to link drug-exposure to tumor-growth-inhibition (TGI) and time-to-tumor progression (TTP) through sVEGFR2 dynamics. The results suggest that 1) active drug concentration (i.e., sunitinib and its metabolite) inhibits the release of sVEGFR2 and that such inhibition is associated with TGI, and 2) daily sVEGFR2 exposure is likely a reliable predictor for the TTP in HCC patients. Moreover, the model quantitatively links the dynamics of an angiogenesis biomarker to TTP and accurately predicts observed literature-reported results of placebo treatment.

The ISoP Standards and Best Practices Committee.

The mission of the International Society of Pharmacometrics (ISoP) Standards and Best Practices Committee is to provide best practices and recommendations for standard pharmacometric analyses-e.g., population pharmacokinetics/pharmacodynamics (PK/PD), exposure-response, disease models-with the goal of increasing consistency, productivity, quality, communication, and impact of pharmacometrics on decision making. We present the progress and plans of the committee and call for volunteers to start new initiatives.

Network-based approaches in drug discovery and early development.

Identification of novel targets is a critical first step in the drug discovery and development process. Most diseases such as cancer, metabolic disorders, and neurological disorders are complex, and their pathogenesis involves multiple genetic and environmental factors. Finding a viable drug target-drug combination with high potential for yielding clinical success within the efficacy-toxicity spectrum is extremely challenging. Many examples are now available in which network-based approaches show potential for the identification of novel targets and for the repositioning of established targets. The objective of this article is to highlight network approaches for identifying novel targets with greater chances of gaining approved drugs with maximal efficacy and minimal side effects. Further enhancement of these approaches may emerge from effectively integrating computational systems biology with pharmacodynamic systems analysis. Coupling genomics, proteomics, and metabolomics databases with systems pharmacology modeling may aid in the development of disease-specific networks that can be further used to build confidence in target identification.

Population pharmacokinetics and dose optimization of mycophenolic acid in HCT recipients receiving oral mycophenolate mofetil.

We sought to create a population pharmacokinetic model for total mycophenolic acid (MPA), to study the effects of different covariates on MPA pharmacokinetics, to create a limited sampling schedule (LSS) to characterize MPA exposure (i.e., area under the curve or AUC) with maximum a posteriori Bayesian estimation, and to simulate an optimized dosing scheme for allogeneic hematopoietic cell transplantation (HCT) recipients. Four thousand four hundred ninety-six MPA concentration-time points from 408 HCT recipients were analyzed retrospectively using a nonlinear mixed effects modeling approach. MPA pharmacokinetics was characterized with a two-compartment model with first-order elimination and a time-lagged first-order absorption process. Concomitant cyclosporine and serum albumin were significant covariates. The median MPA clearance (CL) and volume of the central compartment were 24.2 L/hour and 36.4 L, respectively, for a 70 kg patient receiving tacrolimus with a serum albumin of 3.4 g/dL. Dosing simulations indicated that higher oral MMF doses are needed with concomitant cyclosporine, which increases MPA CL by 33.8%. The optimal LSS was immediately before and at 0.25 hours, 1.25 hours, 2 hours, and 4 hours after oral mycophenolate mofetil administration. MPA AUC in an individual HCT recipient can be accurately estimated using a five-sample LSS and maximum a posteriori Bayesian estimation.

Mechanistic vs. Empirical network models of drug action.

Declining success rates coupled with increased costs is leading to an inevitable breaking point in the drug development pipeline. Can we avoid it by incorporating the vast mechanistic understanding of drug action? A recent review highlights this dilemma and proposes "quantitative logic gate" modeling as a solution.(1) The goal of this commentary is to contrast this approach with mechanistic biochemical network models, which, although alluded to by Kiruoac and Onsum, requires a closer analysis.

Semi-mechanistic population pharmacokinetic model of multivalent trastuzumab emtansine in patients with metastatic breast cancer.

Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate (ADC) composed of multiple molecules of the antimicrotubule agent DM1 linked to trastuzumab, a humanized anti-human epidermal growth factor receptor 2 (HER2) monoclonal antibody. Pharmacokinetics data from phase I (n = 52) and phase II (n = 111) studies in HER2-positive metastatic breast cancer patients show a shorter terminal half-life for T-DM1 than for total trastuzumab (TTmAb). In this work, we translated prior preclinical modeling in monkeys to develop a semi-mechanistic population pharmacokinetics model to characterize T-DM1 and TTmAb concentration profiles. A series of transit compartments with the same disposition parameters was used to describe the deconjugation process from higher to lower drug-to-antibody ratios (DARs). The structure could explain the shorter terminal half-life of T-DM1 relative to TTmab. The final model integrates prior knowledge of T-DM1 DARs from preclinical studies and could provide a platform for understanding and characterizing the pharmacokinetics of other ADC systems.

Bridging Clinical Outcomes of Canakinumab Treatment in Patients With Rheumatoid Arthritis With a Population Model of IL-1ß Kinetics.

Canakinumab, an anti-interleukin-1ß (IL-1ß) monoclonal antibody, is approved for cryopyrin-associated periodic syndromes and is under investigation for the management of other inflammatory disorders. In this study, population-based pharmacokinetic-pharmacodynamic models were developed to understand responses to canakinumab in patients with rheumatoid arthritis (RA). Total canakinumab and total IL-1ß concentrations were obtained from four clinical trials (n = 472). In contrast to traditional models, free IL-1ß concentrations were calculated and used to link canakinumab to changes in C-reactive protein (CRP) concentrations and American College of Rheumatology (ACR) scores of 20, 50, and 70% improvement. Temporal patterns of total canakinumab, total IL-1ß, CRP, and ACR scores were all well described. Simulations confirmed that 150 mg every 4 weeks improved ACR scores in patients with RA, but no additional benefit was provided by higher doses or more frequent administration. Integrating predicted endogenous free ligand concentrations with biomarkers and clinical outcomes could be extended to new therapies of anti-inflammatory diseases.CPT: Pharmacometrics & Systems Pharmacology (2012) 1, e5; doi:10.1038/psp.2012.6; advance online publication 26 September 2012.

Pharmacokinetics and metabolism of (R,R)-methoxyfenoterol in rat.

(R,R)-fenoterol (Fen), a beta(2)-adrenoceptor agonist, is under clinical investigation in the treatment of congestive heart disease. The pharmacokinetics and metabolism of the 4-methoxyphenyl derivative of (R,R)-Fen, (R,R)-MFen, have been determined following intravenous and oral administration to the rat and compared with corresponding results obtained with (R,R)-Fen. Results from the study suggest that (R,R)-MFen can offer pharmacokinetic and metabolic advantages in comparison to an earlier (R,R)-Fen. The oral administration revealed that the net exposure of (R,R)-MFen was about three-fold higher than that of (R,R)-Fen (7.2 versus 2.3 min x nmol ml(-1)), while intravenous administration proved that the clearance was significantly reduced, 48 versus 146 ml min(-1) kg(-1), the T(1/2) was significantly longer, 152.9 versus 108.9 min, and the area under the curve (AUC) was significantly increased, 300 versus 119 min x nmol ml(-1). (R,R)-MFen was primarily cleared by glucuronidation associated with significant presystemic glucuronidation of the compound. After intravenous and oral administration of (R,R)-MFen, (R,R)-Fen and (R,R)-Fen-G were detected in the urine samples indicating that (R,R)-MFen was O-demethylated and subsequently conjugated to (R,R)-Fen-G. The total (R,R)-Fen and (R,R)-Fen-G as a percentage of the dose after intravenous administration was 3.6%, while after oral administration was 0.3%, indicating that only a small fraction of the drug escaped presystemic glucuronidation and was available for O-demethylation. The glucuronidation pattern was confirmed by the results from in vitro studies where incubation of (R,R)-MFen with rat hepatocytes produced (R,R)-MFen-G, (R,R)-Fen and (R,R)-Fen-G, while incubation with rat intestinal microsomes only resulted in the formation of (R,R)-MFen-G.

Development of translational pharmacokinetic-pharmacodynamic models.

Contemporary models in the field of pharmacokinetic-pharmacodynamic (PK-PD) modeling often incorporate the fundamental principles of capacity limitation and operation of turnover processes to describe the time course of pharmacological effects in mechanistic terms. This permits the identification of drug- and system-specific factors that govern drug responses. There is considerable interest in utilizing mechanism-based PK-PD models in translational pharmacology, whereby in silico, in vitro, and preclinical data may be effectively coupled with relevant models to streamline the discovery and development of new therapeutic agents. These translational PK-PD models form the subject of this review.

Pharmacokinetic/pharmacodynamic modeling of renin biomarkers in subjects treated with the renin inhibitor aliskiren.

A semimechanistic pharmacokinetic/pharmacodynamic (PK/PD) model was developed to evaluate the effects of aliskiren on the renin-angiotensin system (RAS) in humans. Mean data were extracted from a three-way crossover, placebo-controlled study. Outcome measures included the time-course of plasma renin activity (PRA) and plasma concentrations of aliskiren, active renin (AR), angiotensin I (ANG I), and angiotensin II (ANG II). The disposition of aliskiren may be best described as a two-compartment model with nonlinear elimination and distribution. The four biomarkers of RAS inhibition were co-modeled, and the AR showed a dose-dependent increase after the administration of aliskiren. This effect was described in terms of an indirect stimulatory response model in conjunction with an empirical submodel of functional adaptation. The estimated concentration of aliskiren necessary for producing 50% inhibition of PRA is 0.66 ng/ml, which is similar to in vitro estimates (0.33 ng/ml) after correction for plasma protein binding. The final and reduced models test the current hypothesis that RAS is inhibited by direct renin antagonism, and also provide suitable platforms for future clinical study design and analysis.

Physical and cognitive performance and burden of anticholinergics, sedatives, and ACE inhibitors in older women.

Polypharmacy, common in older people, confers both risk of adverse outcomes and benefits. We assessed the relationship of commonly prescribed medications with anticholinergic and sedative effects to physical and cognitive performance in older individuals. The study population comprised 932 moderately to severely disabled community-resident women aged 65 years or older who were participants in the Women's Health and Aging Study I. A scale based on pharmacodynamic principles was developed and utilized as a measure of drug burden. This was related to measures of physical and cognitive function. After adjusting for demographics and comorbidities, anticholinergic drug burden was independently associated with greater difficulty in four physical function domains with adjusted odds ratios (95% confidence interval (CI)) of 4.9 (2.0-12.0) for balance difficulty; 3.2 (1.5-6.9) for mobility difficulty; 3.6 (1.6-8.0) for slow gait; 4.2 (2.0-8.7) for chair stands difficulty; 2.4 (1.1-5.3) for weak grip strength; 2.7 (1.3-5.4) for upper extremity limitations; 3.4 (1.7-6.9) for difficulty in activities of daily living; and 2.4 (95% CI, 1.1-5.1) for poor performance on the Mini-Mental State Examination. Sedative burden was associated only with impaired grip strength (3.3 (1.5-7.3)) and mobility difficulty (2.4 (1.1-5.3)). The burden of multiple drugs can be quantified by incorporating the recommended dose regimen and the actual dose and frequency of drug taken. Anticholinergic drug burden is strongly associated with limitations in physical and cognitive function. Sedative burden is associated with impaired functioning in more limited domains. The risk associated with exposure of vulnerable older women to drugs with anticholinergic properties, and to a lesser extent those with sedative properties, implies that such drugs should not be used in this patient group without compelling clinical indication.

A phase I clinical and pharmacokinetic study of the multi-drug resistance protein-1 (MRP-1) inhibitor sulindac, in combination with epirubicin in patients with advanced cancer.

PURPOSE: Multi-drug resistance mediated by ATP-binding cassette trans-membrane protein pumps is an important cause of cancer treatment failure. Sulindac has been shown to be a competitive substrate for the clinically important resistance protein, multi-drug resistance protein-1 (MRP-1), and thus might enhance the anti-cancer activity of substrate chemotherapeutic agents, e.g. anthracyclines. METHODS: We conducted a dose-escalating, single arm, prospective, open label, non-randomised phase I trial of epirubicin (75 mg/m(2)) in combination with escalating oral doses of sulindac (0-800 mg) in patients with advanced cancer to identify an appropriate dose of sulindac to use in future resistance studies. Anthracycline and sulindac pharmacokinetics were studied in cycles 1 and 3. RESULTS: Seventeen patients (8 breast, 3 lung, 2 bowel, 1 melanoma, 1 renal, 1 ovarian and 1 of unknown primary origin, 16/17 having had prior chemotherapy) were enrolled. Eight patients received a full six cycles of treatment; 14 patients received three or more cycles. Dose-limiting toxicity was observed in two patients at 800 mg sulindac (1 renal impairment, 1 fatal haemoptysis in a patient with advanced lung cancer), and sulindac 600 mg was deemed to be the maximum tolerated dose. Sulindac had no effect on epirubicin pharmacokinetics. Among 15 patients with evaluable tumour, two partial responses were seen (malignant melanoma and breast cancer). Four others had prolonged stable disease. CONCLUSION: Epirubicin 75 mg/m(2) and sulindac 600 mg are the recommended doses for phase II studies for these agents in combination.

Impact of first-line vs second-line antibiotics for the treatment of acute uncomplicated sinusitis.

CONTEXT: Studies suggest little benefit in relief of acute sinusitis symptoms from the use of newer and more expensive (second-line) antibiotics instead of older and less expensive (first-line) antibiotics. However, researchers have failed to include development of complications and cost of care in their analyses. OBJECTIVE: To compare the effectiveness and cost of first-line with second-line antibiotics for the treatment of acute uncomplicated sinusitis in adults. DESIGN, SETTING, AND PATIENTS: Retrospective cohort study using a pharmaceutical database containing demographic, clinical (International Classification of Diseases, Ninth Revision), treatment, and charge information for 29 102 adults with a diagnosis of acute sinusitis receiving initial antibiotic treatment between July 1, 1996, and June 30, 1997. MAIN OUTCOME MEASURES: Absence of additional claim for an antibiotic in the 28 days after the initial antibiotic, presence of a claim for a second antibiotic, serious complications of sinusitis, and direct charges and use for the acute sinusitis treatment. RESULTS: There were 17 different antibiotics prescribed in this study. The majority (59.5%) of patients received 1 of the first-line antibiotics. The overall success rate was 90.4% (95% confidence interval [CI], 90.0%-90.8%). The success rate for the 17 329 patients who received a first-line antibiotic was 90.1% and for the 11 773 patients who received a second-line antibiotic was 90.8%, a difference of 0.7% (95% CI, 0.01%-1.40%; P<.05). There were 2 cases of periorbital cellulitis, one in each treatment group. The average total direct charge for patients receiving a first-line antibiotic was $68.98 and a second-line antibiotic was $135.17, a difference of $66.19 (95% CI, $64.95-$67.43; P<.001). This difference was due entirely to the difference in charge of antibiotics and not other charges, such as professional fees, laboratory tests, or emergency department visits. CONCLUSIONS: Patients treated with a first-line antibiotic for acute uncomplicated sinusitis did not have clinically significant differences in outcomes vs those treated with a second-line antibiotic. However, cost of care was significantly higher for patients treated with a second-line antibiotic.

General pharmacokinetic model for drugs exhibiting target-mediated drug disposition.

Drugs that bind with high affinity and to a significant extent (relative to dose) to a pharmacologic target such as an enzyme, receptor, or transporter may exhibit nonlinear pharmacokinetic (PK) behavior. Processes such as receptor-mediated endocytosis may result in drug elimination. A general PK model for characterizing such behavior is described and explored through computer simulations and applications to several therapeutic agents. Simulations show that model predicted plasma concentration vs. time profiles are expected to be polyexponential with steeper distribution phases for lower doses and similar terminal disposition phases. Noncompartmental parameters always show apparent Vss and CL(D) decreasing with dose, but apparent clearance decreases only when the binding process produces drug elimination. The proposed model well captured the time-course of drug concentrations for the aldose reductase inhibitor imirestat, the endothelin receptor antagonist bosentan, and recombinant human interferon-beta 1a. This type of model has a mechanistic basis and considerable utility for fully describing the kinetics for various doses of relevant drugs.

A prospective randomized trial comparing 6 versus 12 prostate biopsy cores: impact on cancer detection.

PURPOSE: Several studies suggest that sextant transrectal ultrasound guided biopsy of the prostate provides insufficient material to detect all clinically important prostate cancer, and obtaining more biopsy cores may improve the cancer detection rate. We performed a prospective randomized trial comparing 6 to 12 prostate biopsy cores to determine the impact on the cancer detection rate. MATERIALS AND METHODS: We prospectively randomized 244 men, including 71 (29%) black men, with a mean age plus or minus standard deviation of 65 +/- 8 years to undergo biopsy with 6 or 12 peripheral zone tissue cores. In our study subjects serum total prostate specific antigen (PSA) was between 2.5 and 20 ng./ml., and/or digital rectal examination was suspicious for cancer. All men completed a self-administered pre-biopsy and 2 post-biopsy questionnaires at 2 and 4 weeks. Cancer detection rates were compared in the groups and correlated with race, biopsy history, digital rectal examination findings, total PSA, transrectal ultrasound volume and PSA density, as determined by the formula, total PSA/transrectal ultrasound volume. RESULTS: The cancer detection rate in the 6 and 12 core groups was almost identical (26% and 27%, p = 0.9). There was no significant difference in cancer detection in the 2 trial arms with respect to subject race, biopsy history, digital rectal examination findings, total PSA, transrectal ultrasound volume or PSA density. However, our study did not have the statistical power to rule out small differences. CONCLUSIONS: The overall cancer detection rate is not materially increased by 12 core, peripheral zone biopsy in men in whom prostate cancer was mainly detected by screening.

The effect of high grade prostatic intraepithelial neoplasia on serum total and percentage of free prostate specific antigen levels.

PURPOSE: It is established that the percentage of free prostate specific antigen (PSA) in serum is low in patients with prostate cancer. An unanswered question is whether a low percentage of free PSA can be explained by high grade prostatic intraepithelial neoplasia alone. We compared the percentage of free PSA in men with high grade prostatic intraepithelial neoplasia alone, prostate cancer, benign prostatic hyperplasia (BPH) and a normal prostate (that is normal digital rectal examination and PSA less than or equal to 2.5 ng./ml.). MATERIALS AND METHODS: From October 1994 through December 1997, 48 men were diagnosed with high grade prostatic intraepithelial neoplasia without concomitant prostate cancer. Of these men 43 with a mean age plus or minus standard deviation of 67.4 +/- 7.8 years comprised our study group. To date none has been diagnosed with cancer during followup. Serum free and total PSA levels were measured, and the percentage of free PSA was calculated. The percentage of free PSA in the 43 men was compared to that in 50 with prostate cancer (mean age 65.4 +/- 7.8 years), 50 with biopsy proved BPH (67 +/- 7) and 43 with a normal prostate (61 +/- 8). RESULTS: There was no significant difference in mean total serum PSA in patients with high grade prostatic intraepithelial neoplasia, prostate cancer or BPH. The percentage of free PSA was significantly lower in patients with prostate cancer (14.9 +/- 6.5%) than those with high grade prostatic intraepithelial neoplasia (20.8 +/- 7.1%), BPH (20.1 +/- 7.3%) or a normal prostate (27.7 +/- 12.2%). There was also no significant difference in the percentage of free PSA between men with high grade prostatic intraepithelial neoplasia (20.8 +/- 7.1%) and those with BPH (20.1 +/- 7.3%). Additionally, men with a normal prostate had a higher percentage of free PSA (27.7%) than those with BPH (20.1%), high grade prostatic intraepithelial neoplasia (20.8%) or prostate cancer (14.9%). CONCLUSIONS: The percentages of free PSA in men with high grade prostatic intraepithelial neoplasia and BPH are similar, and significantly higher than those found in men with prostate cancer.

Potency, continence and complication rates in 1,870 consecutive radical retropubic prostatectomies.

PURPOSE: We update results in a series of consecutive patients treated with anatomic radical retropubic prostatectomy regarding recovery of erections, urinary continence and postoperative complications. MATERIALS AND METHODS: One surgeon performed anatomic radical retropubic prostatectomy on 1,870 men, using the nerve sparing modification when feasible. We evaluated recovery of erections and urinary continence in men followed for a minimum of 18 months. Patients who were not reliably potent before surgery, did not undergo a nerve sparing procedure, or received hormonal therapy or postoperative adjuvant radiotherapy were excluded from the analysis of potency rates but not of continence rates. Other postoperative complications were evaluated for the entire patient population. RESULTS: Recovery of erections occurred in 68% of preoperatively potent men treated with bilateral (543 of 798) and 47% treated with unilateral (28 of 60) nerve sparing surgery. Recovery of erections was more likely with bilateral than with unilateral nerve sparing surgery in patients less than 70 years old (71 versus 48%, p<0.001) compared with patients with age 70 years old or older (48 versus 40%, p = 0.6). Recovery of urinary continence occurred in 92% (1,223 of 1,325 men) and was associated with younger age (p<0.0001) but not with tumor stage (p = 0.2) or nerve sparing surgery (p = 0.3). Postoperative complications occurred in 10% of patients overall and were associated with older age (p<0.002) but the incidence declined significantly with increasing experience of the surgeon (p<0.0001). There was no operative mortality. CONCLUSIONS: Anatomic radical retropubic prostatectomy with the nerve sparing modification can be performed with favorable results in preserving potency and urinary continence. Better results are achieved in young men with organ confined cancer. Other complications can be reduced with increasing surgeon experience.