Pharmacokinetic interactions between natural products (NPs) and conventional medications (prescription and nonprescription) are a longstanding but understudied problem in contemporary ...pharmacotherapy. Consequently, there are no established methods for selecting and prioritizing commercially available NPs to evaluate as precipitants of NP-drug interactions (NPDIs). As such, NPDI discovery remains largely a retrospective, bedside-to-bench process. This Recommended Approach, developed by the Center of Excellence for Natural Product Drug Interaction Research (NaPDI Center), describes a systematic method for selecting NPs to evaluate as precipitants of potential clinically significant pharmacokinetic NPDIs. Guided information-gathering tools were used to score, rank, and triage NPs from an initial list of 47 candidates. Triaging was based on the presence and/or absence of an NPDI identified in a clinical study (≥20% or <20% change in the object drug area under the concentration vs. time curve, respectively), as well as mechanistic and descriptive in vitro and clinical data. A qualitative decision-making tool, termed the fulcrum model, was developed and applied to 11 high-priority NPs for rigorous study of NPDI risk. Application of this approach produced a final list of five high-priority NPs, four of which are currently under investigation by the NaPDI Center.
Display omitted
•Clinical decision support (CDS) for pharmacogenomics (PGx) holds promise.•A novel conceptual framework and measurement model was used to assess pilot PGx-CDS.•This study suggests ...that physicians see a relative advantage to using a pilot PGx-CDS system.•We identify potential improvements to enhance communication effectiveness of PGx-CDS.•We identify potential improvements to enhance the clinical impact of PGx-CDS.
To facilitate personalized drug dosing (PDD), this pilot study explored the communication effectiveness and clinical impact of using a prototype clinical decision support (CDS) system embedded in an electronic health record (EHR) to deliver pharmacogenomic (PGx) information to physicians. We employed a conceptual framework and measurement model to access the impact of physician characteristics (previous experience, awareness, relative advantage, perceived usefulness), technology characteristics (methods of implementation-semi-active/active, actionability-low/high) and a task characteristic (drug prescribed) on communication effectiveness (usefulness, confidence in prescribing decision), and clinical impact (uptake, prescribing intent, change in drug dosing). Physicians performed prescribing tasks using five simulated clinical case scenarios, presented in random order within the prototype PGx-CDS system. Twenty-two physicians completed the study. The proportion of physicians that saw a relative advantage to using PGx-CDS was 83% at the start and 94% at the conclusion of our study. Physicians used semi-active alerts 74–88% of the time. There was no association between previous experience with, awareness of, and belief in a relative advantage of using PGx-CDS and improved uptake. The proportion of physicians reporting confidence in their prescribing decisions decreased significantly after using the prototype PGx-CDS system (p=0.02). Despite decreases in confidence, physicians perceived a relative advantage to using PGx-CDS, viewed semi-active alerts on most occasions, and more frequently changed doses toward doses supported by published evidence. Specifically, sixty-five percent of physicians reduced their dosing, significantly for capecitabine (p=0.002) and mercaptopurine/thioguanine (p=0.03). These findings suggest a need to improve our prototype such that PGx CDS content is more useful and delivered in a way that improves physician’s confidence in their prescribing decisions. The greatest increases in communication effectiveness and clinical impact of PGx-CDS are likely to be realized through continued focus on content, content delivery, and tailoring to physician characteristics.
Introduction
Medication nonadherence continues to be challenging for allogeneic hematopoietic cell transplant (HCT) recipients. The risk and severity of chronic graft-versus-host disease (GVHD) are ...associated with low immunosuppressant concentrations (which can be improved with model-informed precision dosing (MIPD)) and with immunosuppressant nonadherence (which can be improved with acceptable interventions).
Methods
With the goals of improving adherence and achieving therapeutic concentrations of immunosuppressants to eliminate GVHD, we characterized the feasibility of using the Medication Event Monitoring (MEMS®) Cap in adult HCT recipients.
Results
Of the 27 participants offered the MEMS® Cap at the time of hospital discharge, 7 (25.9%) used it, which is below our a priori threshold of 70%. These data suggest the MEMS® Cap is not feasible for HCT recipients. The MEMS® Cap data were available for a median of 35 days per participant per medication (range: 7–109 days). The average daily adherence per participant ranged from 0 to 100%; four participants had an average daily adherence of over 80%.
Conclusions
MIPD may be supported by MEMS® technology to provide the precise time of immunosuppressant self-administration. The MEMS® Cap was used by only a small percentage (25.9%) of HCT recipients in this pilot study. In accordance with larger studies using less accurate tools to evaluate adherence, immunosuppressant adherence varied from 0% to 100%. Future studies should establish the feasibility and clinical benefit of combining MIPD with newer technology, specifically the MEMS® Button, which can inform the oncology pharmacist of the time of immunosuppressant self-administration.
This issue of Clinical Pharmacology & Therapeutics focuses on emerging infections. The outbreaks of the vaccine‐preventable diseases (e.g., measles) and the emerging pathogens (e.g., Ebola) show us ...how small the world has become. These outbreaks also show the pressing need for effective public education and development of novel therapies. This issue covers various aspects of relevant therapeutic topics ranging from preclinical models, pharmacokinetics, pharmacodynamics, pharmacogenomics, and clinical trial results, to education efforts in this area. Pharmacokinetic/dynamic modeling had an appreciable role in reducing the morbidity and mortality associated with human immunodeficiency virus and hepatitis C virus, recent emerging infections. However, these gains could be lessened by poor adherence to therapies, which has contributed to the development of multidrug‐resistant tuberculosis. We must not forget lessons from previous infections, or they may reemerge.
During puberty, a woman's breasts are vulnerable to environmental damage ("window of vulnerability"). Early exposure to environmental carcinogens, endocrine disruptors, and unhealthy foods (refined ...sugar, processed fats, food additives) are hypothesized to promote molecular damage that increases breast cancer risk. However, prospective human studies are difficult to perform and effective interventions to prevent these early exposures are lacking. It is difficult to prevent environmental exposures during puberty. Specifically, young women are repeatedly exposed to media messaging that promotes unhealthy foods. Young women living in disadvantaged neighborhoods experience additional challenges including a lack of access to healthy food and exposure to contaminated air, water, and soil. The purpose of this review is to gather information on potential exposures during puberty. In future directions, this information will be used to help elementary/middle-school girls to identify and quantitate environmental exposures and develop cost-effective strategies to reduce exposures.
High‐dose busulfan is frequently used in a variety of conditioning regimens for hematopoietic cell transplantation. In this setting, busulfan has marked neurotoxicity, specifically causing seizures ...that generally are tonic‐clonic in character. Phenytoin has been the preferred drug to treat busulfan‐induced seizures, but this practice should be reexamined in light of newer antiepileptic drugs being preferentially used by neurologists. Characteristics of ideal seizure prophylaxis include lack of overlapping toxicity with the conditioning regimen, lack of interference with engraftment of donor cells, and minimal potential for pharmacokinetic drug interactions. Based on these criteria, phenytoin is suboptimal due to possible toxicities and is especially ill suited because of its ability to induce busulfan metabolism. It is postulated that this induction adversely affects efforts to update methods for targeting busulfan doses to individual patients, based on recent developments in the understanding of the pharmacogenomics of busulfan metabolism. The existing clinical data support the use of benzodiazepines, most notably clonazepam and lorazepam, to prevent busulfan‐induced seizures. The second‐generation antiepileptic drug levetiracetam possesses the characteristics of optimal prophylaxis for busulfan‐induced seizures, and early data of its efficacy are promising, although further study is needed.
Currently, tamoxifen is the only drug approved for reduction of breast cancer risk in premenopausal women. The significant cardiovascular side effects of tamoxifen, coupled with lack of a survival ...benefit, potential for genotoxicity, and failure to provide a significant risk-reduction for estrogen receptor-negative breast cancer, all contribute to the low acceptance of tamoxifen chemoprevention in premenopausal women at high-risk for breast cancer. While other prevention options exist for postmenopausal women, there is a search for well-tolerated prevention agents that can simultaneously reduce risk of breast cancers, cardiovascular disease, and type-2 diabetes. Metformin is a well-tolerated oral biguanide hypoglycemic agent that is prescribed worldwide to over 120 million individuals with type-2 diabetes. Metformin is inexpensive, safe during pregnancy, and the combination of metformin, healthy lifestyle, and exercise has been shown to be effective in preventing diabetes. There is a growing awareness that prevention drugs and interventions should make the "whole woman healthy." To this end, current efforts have focused on finding low toxicity alternatives, particularly repurposed drugs for chemoprevention of breast cancer, including metformin. Metformin's mechanisms of actions are complex but clearly involve secondary lowering of circulating insulin. Signaling pathways activated by insulin also drive biologically aggressive breast cancer and predict poor survival in women with breast cancer. The mechanistic rationale for metformin chemoprevention is well-supported by the scientific literature. Metformin is cheap, safe during pregnancy, and has the potential to provide heart-healthy breast cancer prevention. On-going primary and secondary prevention trials will provide evidence whether metformin is effective in preventing breast cancer.
Aprepitant, a neurokinin antagonist, is an effective antiemetic agent in chemotherapy for delayed nausea and vomiting. The study objective was to evaluate the pharmacokinetics of aprepitant and ...concurrent cyclophosphamide (CY), often a component of hematopoietic stem cell transplant (HSCT) conditioning regimen, in cancer patients undergoing HSCT. Forty subjects were randomized to either aprepitant or placebo in addition to standard antiemetics. Aprepitant or placebo was started 1 hour before the first chemotherapy or radiation dose for HSCT conditioning and administered daily until 4 days after infusion of the hematopoietic cell graft (for a total of 10-12 days). Serial blood samples were collected for aprepitant and CY plus 2 important CY metabolites. The results indicate that aprepitant is well absorbed and does not auto-induce its metabolism. No significant drug interaction was observed with CY or its metabolites. A significant portion of the patients had subtherapeutic aprepitant concentrations; however, chemotherapy-induced nausea and vomiting were effectively managed. No dosage adjustment was necessary, and administration of aprepitant in HSCT at the prescribed dosage of 125 mg orally on day 1 and 80 mg orally on each consecutive day through day +4 after HSCT was well tolerated with no significant changes in CY pharmacokinetic parameters.
Personalizing busulfan doses to target a narrow plasma exposure has improved the efficacy and lowered the toxicity of busulfan-based conditioning regimens used in hematopoietic cell transplant. ...Regional regulations guide interlaboratory proficiency testing for busulfan concentration quantification and monitoring. To date, there have been no comparisons of the busulfan pharmacokinetic modeling and dose recommendation protocols used in these laboratories. Here, in collaboration with the Dutch Association for Quality Assessment in Therapeutic Drug Monitoring and Clinical Toxicology, a novel interlaboratory proficiency program for the quantitation in plasma, pharmacokinetic modeling, and dosing of busulfan was designed. The methods and results of the first 2 rounds of this proficiency testing are described herein.
A novel method was developed to stabilize busulfan in N,N-dimethylacetamide, which allowed shipping of the proficiency samples without dry ice. In each round, participating laboratories reported their results for 2 proficiency samples (one low and one high busulfan concentrations) and a theoretical case assessing their pharmacokinetic modeling and dose recommendations. All participants were blinded to the answers; descriptive statistics were used to evaluate their overall performance. The guidelines suggested that answers within ±15% for busulfan concentrations and ±10% for busulfan plasma exposure and dose recommendation were to be considered accurate.
Of the 4 proficiency samples evaluated, between 67% and 85% of the busulfan quantitation results were accurate (ie, within 85%-115% of the reference value). The majority (88% round #1; 71% round #2) of the dose recommendation answers were correct.
A proficiency testing program by which laboratories are alerted to inaccuracies in their quantitation, pharmacokinetic modeling, and dose recommendations for busulfan in hematopoietic cell transplant recipients was developed. These rounds of proficiency testing suggests that additional educational efforts and proficiency rounds are needed to ensure appropriate busulfan dosing.
Purpose
We developed a new population pharmacokinetic (PopPK) model for intravenous (i.v.) busulfan in children to evaluate the optimal method to personalize its dosing without concentration-time ...data.
Methods
PopPK analyses were done with NONMEM® 7.2. First, a model from Trame et al. was evaluated using an external dataset consisting of 24 children. Second, a revised model was built in a separate dataset of 82 children. Model evaluation was performed by using a standardized visual predictive check (SVPC) procedure and a bootstrap analysis (internal evaluation) and by comparison to an external dataset (external validation).
Results
The final model included body surface area (BSA) as an exponential function on volume of distribution (V) and actual body weight (ABW) as an allometric function on clearance (CL). The dosing nomogram for every 6 h administration derived from the final model is: dosemg = target AUCmg × h/L × 3.04L/h × (ABW/16.1)
0.797
. Compared to other dosing strategies, differences were observed for the very small and obese patients.
Conclusions
We revised our prior dosing nomogram after validation in a separate cohort of children. This dosing nomogram can be used to personalize i.v. busulfan doses without concentration-time data, but an additional prospective evaluation in the very small and obese children is needed.
PDF
