A new frontier in haematology – combining pharmacokinetic with pharmacodynamic factors to improve choice and dose of drug

Arpon, David; Gandhi, Maher K.; Martin, Jennifer

doi:10.1111/bcp.12318

Cited by 8 publications

(5 citation statements)

References 55 publications

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“…Arpon et al [34] maintain that dosing adjusted according to a range of patient-specific factors is of large and increasing clinical and financial concern but lament that the amount of body weight adjusted dosing change that occurs in clinical practice is presently unknown. Adjustments for body mass in most cases do not ameliorate the high incidence of female ADRs.…”

Section: Reasons Why Men and Women Respond Differently To Drugsmentioning

confidence: 99%

Sex differences in pharmacokinetics predict adverse drug reactions in women

2020

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Background: Women experience adverse drug reactions, ADRs, nearly twice as often as men, yet the role of sex as a biological factor in the generation of ADRs is poorly understood. Most drugs currently in use were approved based on clinical trials conducted on men, so women may be overmedicated. We determined whether sex differences in drug pharmacokinetics, PKs, predict sex differences in ADRs. Methods: Searches of the ISI Web of Science and PubMed databases were conducted with combinations of the terms: drugs, sex or gender, pharmacokinetics, pharmacodynamics, drug safety, drug dose, and adverse drug reaction, which yielded over 5000 articles with considerable overlap. We obtained information from each relevant article on significant sex differences in PK measures, predominantly area under the curve, peak/maximum concentrations, and clearance/elimination rates. ADRs were identified from every relevant article and recorded categorically as female-biased, male-biased, or not sex-biased. Results: For most of the FDA-approved drugs examined, elevated blood concentrations and longer elimination times were manifested by women, and these PKs were strongly linked to sex differences in ADRs. Of the 86 drugs evaluated, 76 had higher PK values in women; for 59 drugs with clinically identifiable ADRs, sex-biased PKs predicted the direction of sex-biased ADRs in 88% of cases. Ninety-six percent of drugs with female-biased PK values were associated with a higher incidence of ADRs in women than men, but only 29% of male-biased PKs predicted male-biased ADRs. Accessible PK information is available for only a small fraction of all drugs Conclusions: Sex differences in pharmacokinetics strongly predict sex-specific ADRs for women but not men. This sex difference was not explained by sex differences in body weight. The absence of sex-stratified PK information in public records for hundreds of drugs raises the concern that sex differences in PK values are widespread and of clinical significance. The common practice of prescribing equal drug doses to women and men neglects sex differences in pharmacokinetics and dimorphisms in body weight, risks overmedication of women, and contributes to female-biased adverse drug reactions. We recommend evidence-based dose reductions for women to counteract this sex bias.

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Section: Reasons Why Men and Women Respond Differently To Drugsmentioning

confidence: 99%

Sex differences in pharmacokinetics predict adverse drug reactions in women

2020

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“…13 Not only do NK cells exert direct cytotoxicity against tumor cells, but in NHL, this effect is indirectly enhanced through therapeutic monoclonal antibodies. 14 Conventionally, circulating NK cells are phenotypically divided into 2 functional subsets on the basis of their surface expression of CD16 (FcgRIII) and CD56 (neural cell adhesion molecule 1) surface markers. 15 CD3 2 CD56 dim CD16 1 ("CD16 1 ") typically form up to 95% of the total NK-cell population and are cytotoxic and mediate antibody dependant cellular cytotoxicity (ADCC).…”

Section: Introductionmentioning

confidence: 99%

Immune evasion via PD-1/PD-L1 on NK cells and monocyte/macrophages is more prominent in Hodgkin lymphoma than DLBCL

Vari

Arpon

Keane

et al. 2018

Blood

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260

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Much focus has been on the interaction of programmed cell death ligand 1 (PD-L1) on malignant B cells with programmed cell death 1 (PD-1) on effector T cells in inhibiting antilymphoma immunity. We sought to establish the contribution of natural killer (NK) cells and inhibitory CD163 monocytes/macrophages in Hodgkin lymphoma (cHL) and diffuse large B-cell lymphoma (DLBCL). Levels of PD-1 on NK cells were elevated in cHL relative to DLBCL. Notably, CD3CD56CD16 NK cells had substantially higher PD-1 expression relative to CD3CD56CD16 cells and were expanded in blood and tissue, more marked in patients with cHL than patients with DLBCL. There was also a raised population of PD-L1-expressing CD163 monocytes that was more marked in patients with cHL compared with patients with DLBCL. The phenotype of NK cells and monocytes reverted back to normal once therapy (ABVD [doxorubicin 25 mg/m, bleomycin 10 000 IU/m, vinblastine 6 mg/m, dacarbazine 375 mg/m, all given days 1 and 15, repeated every 28 days] or R-CHOP [rituximab 375 mg/m, cyclophosphamide 750 mg/m IV, doxorubicin 50 mg/m IV, vincristine 1.4 mg/m (2 mg maximum) IV, prednisone 100 mg/day by mouth days 1-5, pegfilgrastim 6 mg subcutaneously day 4, on a 14-day cycle]) had commenced. Tumor-associated macrophages (TAMs) expressed high levels of PD-L1/PD-L2 within diseased lymph nodes. Consistent with this, CD163/PD-L1/PD-L2 gene expression was also elevated in cHL relative to DLBCL tissues. An in vitro functional model of TAM-like monocytes suppressed activation of PD-1 NK cells, which was reversed by PD-1 blockade. In line with these findings, depletion of circulating monocytes from the blood of pretherapy patients with cHL and patients with DLBCL enhanced CD3CD56CD16 NK-cell activation. We describe a hitherto unrecognized immune evasion strategy mediated via skewing toward an exhausted PD-1-enriched CD3CD56CD16 NK-cell phenotype. In addition to direct inhibition of NK cells by the malignant B cell, suppression of NK cells can occur indirectly by PD-L1/PD-L2-expressing TAMs. The mechanism is more prominent in cHL than DLBCL, which may contribute to the clinical sensitivity of cHL to PD-1 blockade.

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“…Pertinent considerations also include the reliability of surface area-or weight-based dose calculation to normalize systemic concentrations between patients, and the effect of biologic factors on the pharmacokinetics and pharmacodynamics of therapy. 20,21 Surface area and weight-based dosing do not achieve a precise degree of systemic concentration normalization due to interpatient pharmacokinetics of most products. Pharmacokinetic studies demonstrate a notable coefficient of variation for the area under the concentration versus time curve for most biologic products: ado-trastuzumab, 11%-34%; 22,23 bevacizumab, 15%-53%; [24][25][26] brentuximab, 25%-30%; 27 cetuximab, 22%-65%; [28][29][30] ipilimumab, 25%-36%; 31 rituximab, 45%; 32,33 trastuzumab, 25%-35%; 34 and zivaflibercept, 15%-37%.…”

Section: Discussionmentioning

confidence: 99%

Cost avoidance from dose rounding biologic and cytotoxic antineoplastics

VanDyke

Athmann

Ballmer

et al. 2016

J Oncol Pharm Pract

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Background To reduce product wastage, our institution allows automatic dose rounding of biologic and cytotoxic anticancer agents. The purpose of this project was to determine the actual annual cost avoidance due to pharmacist-managed automatic dose rounding of anticancer treatments. Methods Financial impact was assessed within the context of our departmental standard work which supports automatic dose rounding of biologic anticancer agents (±10%) and cytotoxic anticancer agents (±5%) to the nearest vial size for body surface area- or weight-based doses. Exclusions to automatic dose rounding include multiple dose vial products, pediatric orders, clinical trial drugs, and parenteral busulfan. The amount of cost avoidance for each rounded dose was determined using the product acquisition cost of the smallest available product amount. Data were collected from anticancer treatment orders for the fiscal year 1 July 2013 to 30 June 2014. Results A total of 6216 doses of anticancer drugs were checked for dose rounding during the period of data collection. Almost $200,000 in product acquisition cost was avoided with pharmacist-managed automatic dose rounding. Six different biologic products accounted for approximately 7% of the total doses analyzed and 78% of the cost avoidance. Fifteen drugs comprised the array of cytotoxic agents rounded. Approximately, 37% and 4% of the biologic and cytotoxic doses were rounded up to the vial size. Conclusion Routine dose rounding of biologic anticancer agents (±10%) and cytotoxic products (±5%) achieved cost avoidance through reduction of drug wastage at our institution.

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A new frontier in haematology – combining pharmacokinetic with pharmacodynamic factors to improve choice and dose of drug

Cited by 8 publications

References 55 publications

Sex differences in pharmacokinetics predict adverse drug reactions in women

Sex differences in pharmacokinetics predict adverse drug reactions in women

Immune evasion via PD-1/PD-L1 on NK cells and monocyte/macrophages is more prominent in Hodgkin lymphoma than DLBCL

Cost avoidance from dose rounding biologic and cytotoxic antineoplastics

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