Part I of this article included a pertinent review of allogeneic hematopoietic cell transplantation (alloHCT), the role of postgraft immunosuppression in alloHCT, and the pharmacokinetics, ...pharmacodynamics, and pharmacogenomics of the calcineurin inhibitors and methotrexate. In this article (Part II), we review the pharmacokinetics, pharmacodynamics, and pharmacogenomics of mycophenolic acid (MPA), sirolimus, and the antithymocyte globulins (ATG). We then discuss target concentration intervention (TCI) of these postgraft immunosuppressants in alloHCT patients, with a focus on current evidence for TCI and on how TCI may improve clinical management in these patients. Currently, TCI using trough concentrations is conducted for sirolimus in alloHCT patients. Several studies demonstrate that MPA plasma exposure is associated with clinical outcomes, with an increasing number of alloHCT patients needing TCI of MPA. Compared with MPA, there are fewer pharmacokinetic/dynamic studies of rabbit ATG and horse ATG in alloHCT patients. Future pharmacokinetic/dynamic research of postgraft immunosuppressants should include '-omics'-based tools: pharmacogenomics may be used to gain an improved understanding of the covariates influencing pharmacokinetics as well as proteomics and metabolomics as novel methods to elucidate pharmacodynamic responses.
Purpose Intermediate-risk rhabdomyosarcoma (RMS) includes patients with either nonmetastatic, unresected embryonal RMS (ERMS) with an unfavorable primary site or nonmetastatic alveolar RMS (ARMS). ...The primary aim of this study was to improve the outcome of patients with intermediate-risk RMS by substituting vincristine and irinotecan (VI) for half of vincristine, dactinomycin, and cyclophosphamide (VAC) courses. All patients received a lower dose of cyclophosphamide and earlier radiation therapy than in previous trials. Patients and Methods Patients were randomly assigned at study entry to either VAC (cumulative cyclophosphamide dose, 16.8 g/m
) or VAC/VI (cumulative cyclophosphamide dose, 8.4 g/m
) for 42 weeks of therapy. Radiation therapy started at week 4, with individualized local control plans permitted for patients younger than 24 months. The primary study end point was event-free survival (EFS). The study design had an 80% power (5% one-sided α-level) to detect an improved long-term EFS from 65% (with VAC) to 76% (with VAC/VI). Results A total of 448 eligible patients were enrolled in the study. At a median follow-up of 4.8 years, the 4-year EFS was 63% with VAC and 59% with VAC/VI ( P = .51), and 4-year overall survival was 73% for VAC and 72% for VAC/VI ( P = .80). Within the ARMS and ERMS subgroups, no difference in outcome by treatment arm was found. Severe hematologic toxicity was less common with VAC/VI therapy. Conclusion The addition of VI to VAC did not improve EFS or OS for patients with intermediate-risk RMS. VAC/VI had less hematologic toxicity and a lower cumulative cyclophosphamide dose, making VAC/VI an alternative standard therapy for intermediate-risk RMS.
The mTOR inhibitor sirolimus is prescribed to treat children with varying diseases, ranging from vascular anomalies to sporadic lymphangioleiomyomatosis to transplantation (solid organ or ...hematopoietic cell). Precision dosing of sirolimus using therapeutic drug monitoring (TDM) of sirolimus concentrations in whole blood drawn at the trough (before the next dose) time-point is the current standard of care. For sirolimus, trough concentrations are only modestly correlated with the area under the curve, with
values ranging from 0.52 to 0.84. Thus, it should not be surprising, even with the use of sirolimus TDM, that patients treated with sirolimus have variable pharmacokinetics, toxicity, and effectiveness. Model-informed precision dosing (MIPD) will be beneficial and should be implemented. The data do not suggest dried blood spots point-of-care sampling of sirolimus concentrations for precision dosing of sirolimus. Future research on precision dosing of sirolimus should focus on pharmacogenomic and pharmacometabolomic tools to predict sirolimus pharmacokinetics and wearables for point-of-care quantitation and MIPD.
Sales of botanical dietary supplements and other purported medicinal natural products (NPs) have escalated over the past ∼25 years, increasing the potential for NPs to precipitate clinically ...significant pharmacokinetic interactions with U.S. Food and Drug Administration-approved medications NP-drug interactions (NPDIs). However, published NPDI studies to date often lack consistency in design, implementation, and documentation, which present difficulties in assessing the clinical significance of the results. Common hurdles include large variability in the admixture composition of phytoconstituents between and within batches of a given NP, limited knowledge on the pharmacokinetics of precipitant NP constituents, and use of animal and/or in vitro models which, in some cases, are not mechanistically appropriate for extrapolation to humans. The National Center for Complementary and Integrative Health created a Center of Excellence for Natural Product-Drug Interaction Research (NaPDI Center) to address these unmet research needs. The NaPDI Center has two overarching goals: 1) develop Recommended Approaches to guide researchers in the proper conduct of NPDI studies, which will evolve over time concurrent with emerging technologies and new research data, and 2) apply the Recommended Approaches in evaluating four model NPs as precipitants of NPDIs with clinically relevant object drugs. The major objectives of this commentary are to 1) explain the rationale for creating the NaPDI Center; 2) describe the decision trees developed by the NaPDI Center to enhance the planning, rigor, and consistency of NPDI studies; and 3) provide a framework for communicating results to the multidisciplinary scientists interested in the NaPDI Center's interaction projects.
Pharmacogenomics (PGx), the study of inherited genomic variation and drug response or safety, is a vital tool in precision medicine. In oncology, testing to identify PGx variants offers patients the ...opportunity for customized treatments that can minimize adverse effects and maximize the therapeutic benefits of drugs used for cancer treatment and supportive care. Because individuals of shared ancestry share specific genetic variants, PGx factors may contribute to outcome disparities across racial and ethnic categories when genetic ancestry is not taken into account or mischaracterized in PGx research, discovery, and application. Here, we examine how the current scientific understanding of the role of PGx in differential oncology safety and outcomes may be biased toward a greater understanding and more complete clinical implementation of PGx for individuals of European descent compared with other genetic ancestry groups. We discuss the implications of this bias for PGx discovery, access to care, drug labeling, and patient and provider understanding and use of PGx approaches. Testing for somatic genetic variants is now the standard of care in treatment of many solid tumors, but the integration of PGx into oncology care is still lacking despite demonstrated actionable findings from PGx testing, reduction in avoidable toxicity and death, and return on investment from testing. As the field of oncology is poised to expand and integrate germline genetic variant testing, it is vital that PGx discovery and application are equitable for all populations. Recommendations are introduced to address barriers to facilitate effective and equitable PGx application in cancer care.
Intravenous busulfan doses are often personalized to a target plasma exposure (targeted busulfan) using an individual’s busulfan clearance (BuCL). We evaluated whether BuCL could be predicted by a ...predose plasma panel of 841 endogenous metabolomic compounds (EMCs). In this prospective cohort of 132 hematopoietic cell transplantation (HCT) patients, all had samples collected immediately before busulfan administration (preBU) and 96 had samples collected 2 weeks before busulfan (2‐week‐preBU). BuCL was significantly associated with 37 EMCs after univariate linear regression analysis and controlling for false discovery (< 0.05) in the 132 preBU samples. In parallel, with preBU samples, we included all 841 EMCs in a least absolute shrinkage and selection operator–penalized regression which selected 13 EMCs as predominantly associated with BuCL. Then, we constructed a prediction model by estimating coefficients for these 13 EMCs, along with sex, using ordinary least‐squares. When the resulting linear prediction model was applied to the 2‐week‐preBU samples, it explained 40% of the variation in BuCL (adjusted R2 = 0.40). Pathway enrichment analysis revealed 18 pathways associated with BuCL. Lysine degradation followed by steroid biosynthesis, which aligned with the univariate analysis, were the top two pathways. BuCL can be predicted before busulfan administration with a linear regression model of 13 EMCs. This pharmacometabolomics method should be prioritized over use of a busulfan test dose or pharmacogenomics to guide busulfan dosing. These results highlight the potential of pharmacometabolomics as a precision medicine tool to improve or replace pharmacokinetics to personalize busulfan doses.
The clinical outcomes of busulfan-based conditioning regimens for hematopoietic cell transplantation (HCT) have been improved by personalizing the doses to target narrow busulfan plasma exposure. An ...interlaboratory proficiency test program for the quantitation, pharmacokinetic modeling, and busulfan dosing in plasma was developed. Previous proficiency rounds (ie, the first 2) found that 67%-85% and 71%-88% of the dose recommendations were inaccurate, respectively.
A proficiency test scheme was developed by the Dutch Foundation for Quality Assessment in Medical Laboratories (SKML) and consisted of 2 rounds per year, with each round containing 2 busulfan samples. In this study, 5 subsequent proficiency tests were evaluated. In each round, the participating laboratories reported their results for 2 proficiency samples (ie, low and high busulfan concentrations) and a theoretical case assessing their pharmacokinetic modeling and dose recommendations. Descriptive statistics were performed, with ±15% for busulfan concentrations and ±10% for busulfan plasma exposure. The dose recommendations were deemed accurate.
Since January 2020, 41 laboratories have participated in at least 1 round of this proficiency test. Over the 5 rounds, an average of 78% of the busulfan concentrations were accurate. Area under the concentration-time curve calculations were accurate in 75%-80% of the cases, whereas only 60%-69% of the dose recommendations were accurate. Compared with the first 2 proficiency test rounds (PMID 33675302, October, 2021), the busulfan quantitation results were similar, but the dose recommendations worsened. Some laboratories repeatedly submit results that deviated by more than 15% from the reference values.
The proficiency test showed persistent inaccuracies in busulfan quantitation, pharmacokinetic modeling, and dose recommendations. Additional educational efforts have yet to be implemented; regulatory efforts seem to be needed. The use of specialized busulfan pharmacokinetic laboratories or a sufficient performance in busulfan proficiency tests should be required for HCT centers that prescribe busulfan.
Background
In vitro data suggest that the growth of rhabdomyosarcoma (RMS) cells is suppressed in a concentration‐dependent manner by 4‐hydroxycyclophosphamide (4HCY), the principal precursor to the ...cytotoxic metabolite of cyclophosphamide (CY). Various retrospective studies on the relationship between genes encoding proteins involved in the formation and elimination of 4HCY (i.e., 4HCY pharmacokinetics) and cyclophosphamide (CY) efficacy and toxicity have been conflicting.
Procedures
We evaluated germline pharmacogenetics in 262 patients with newly diagnosed intermediate‐risk RMS who participated in one prospective Children's Oncology Group clinical trial, ARST0531. Patients were treated with either vincristine/actinomycin/cyclophosphamide (VAC) or VAC alternating with vincristine/irinotecan (VAC/VI). We analyzed the associations between event‐free survival and 394 single‐nucleotide polymorphisms (SNP) in 14 drug metabolizing enzymes or transporters involved in 4HCY pharmacokinetics.
Results
Eight SNPs were associated (p‐value < .05 by univariate analysis) with 3‐year event‐free survival; no SNPs survived a false discovery rate < 0.05.
Conclusions
Our data suggest that a pharmacogenomic approach to therapy personalization of cyclophosphamide in intermediate‐risk rhabdomyosarcoma is not viable. Other methods to personalize therapy should be explored.
There are many gaps in scientific knowledge about the clinical significance of pharmacokinetic natural product-drug interactions (NPDIs) in which the natural product (NP) is the precipitant and a ...conventional drug is the object. The National Center for Complimentary and Integrative Health created the Center of Excellence for NPDI Research (NaPDI Center) (www.napdi.org) to provide leadership and guidance on the study of pharmacokinetic NPDIs. A key contribution of the Center is the first user-friendly online repository that stores and links pharmacokinetic NPDI data across chemical characterization, metabolomics analyses, and pharmacokinetic in vitro and clinical experiments (repo.napdi.org). The design is expected to help researchers more easily arrive at a complete understanding of pharmacokinetic NPDI research on a particular NP. The repository will also facilitate multidisciplinary collaborations, as the repository links all of the experimental data for a given NP across the study types. The current work describes the design of the repository, standard operating procedures used to enter data, and pharmacokinetic NPDI data that have been entered to date. To illustrate the usefulness of the NaPDI Center repository, more details on two high-priority NPs, cannabis and kratom, are provided as case studies. SIGNIFICANCE STATEMENT: The data and knowledge resulting from natural product-drug interaction (NPDI) studies is distributed across a variety of information sources, rendering difficulties to find, access, and reuse. The Center of Excellence for NPDI Research addressed these difficulties by developing the first user-friendly online repository that stores data from in vitro and clinical pharmacokinetic NPDI experiments and links them with study data from chemical characterization and metabolomics analyses of natural products that are also stored in the repository.
At Massachusetts General Hospital, we pioneered simultaneous hematopoietic cell (HCT)/kidney transplantation from HLA-identical related donors for the treatment of hematological malignancies with ...end-stage renal failure. We have now extended this to HLA-haploidentical donors in a pilot trial. Six recipients, 5 of whom were conditioned with fludarabine, cyclophosphamide, and total-body irradiation, underwent combined HCT/kidney transplantation from haploidentical donors; graft-versus-host disease (GVHD) prophylaxis included post-HCT cyclophosphamide, tacrolimus, and mycophenolate mofetil. One patient died as a result of complications of fludarabine neurological toxicity. No neurological toxicity was observed in subsequent patients who received lower fludarabine doses and more intense postfludarabine dialysis. There were no cases of grade 2 to 4 acute GVHD and 1 case of moderate chronic GVHD by 12 months. One patient experienced relapse of multiple myeloma at 30 months after HCT and died 4 years posttransplantation. Overall, 4 of 6 patients remain alive, without disease relapse and with long-term renal rejection–free survival. This trial was registered at www.clinicaltrials.gov as #NCT01758042.
•Combined haploidentical HCT/kidney transplantation is safe and feasible with posttransplantation cyclophosphamide.•Fludarabine can be used for conditioning in patients with end-stage renal disease if proper dose adjustments and dialysis are used.
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