[ ISSN : 2573-3680 ]
Normalization; Optimization; Lipophilic drugs; Hydrophilic drugs; Anti-cancer drugs
Patient dose normalization for optimal doses found in phase 1 clinical trials remains underutilized in Clinical Oncology. The Body Surface Area (BSA) is dominant despite its lack of rigor, apparent inadequacies and the frequent need for dose adjustment. The BSA method has been critiqued over the decades. In this paper, the use of In vivo body composition methods to determine fat mass and fat free mass are proposed, which would form the new basis for normalization of lipophilic and hydrophilic drugs. Issues relating to volume of distribution and drug clearance remain largely unknown, but at least the starting patient dose is expected to be better placed. Clinical trials are needed to justify both this approach and the BSA method
The distribution of drugs from the injection site by the vascular system to the target tissue is governed by blood flow, solubility, binding to macromolecules and ability to cross special barriers. Drugs can be hydrophilic or lipophilic or both. Lipophilic drugs can pass through cell membranes due to their solubility in membrane bilayers but not so hydrophilic drugs, which require aqueous channels or pores. Large molecules require endocytosis, which entails engulfment of the molecule and transport into the cell by pinching off the drug filled vesicle.
Bioavailability is the fraction of the injected dose that reaches the systemic circulation with unchanged properties. The extent of drug absorption can be measured by the Area under the Curve (AUC) for plasma concentrations over time. For hydrophilic drugs, the concentration depends on the volume of distribution of the Total Body Water (TBW).
TBW and other body compartments have been studied by In vivo body composition in many medical conditions in the 1980s. However, current Oncology dose protocols have not moved on from either Body Surface Area (BSA) or Body Mass (BM) in the normalization of dose for each patient. Anticancer drugs have a narrow therapeutic window and significant patient variability in therapeutic and toxic effects. As such, it is important that dose optimization is achieved. This paper reviews the evidence against using BSA and proposes an alternative dose normalization approach that uses the Fat Free Mass (FFM) for hydrophilic drugs.
Body Surface Area
BSA plays a key role in several medical fields, including cancer chemotherapy, transplantology, burn treatment and toxicology. BSA is often a major factor in the determination of the course of treatment and drug dosage. Mathematical formulae to calculate BSA from measurements of height, weight and other parameters date from the late 19th century [1]. Drug doses, fluid therapy, caloric requirements and physiological parameters such as cardiac output, glomerular filtration rate and a variety of respiratory function parameters are all frequently expressed in terms of a BSA, which is often used in preference to BM. The calculated surface area of a human body may be a better indicator of metabolic mass than body weight because it is less affected by abnormal adipose mass [2].
The simplest formula is: 
Just how this relates to metabolic mass is unclear. However, the original rationale for using body surface area as an estimate for metabolic rate has never been tested and the algorithms used to approximate body surface area have little evidence to support their use in this role. Recent developments in technology using indirect calorimetry allow easy measurement of metabolic rate in the clinical setting. Such measurements should be used for standardization when weight alone is considered inadequate.
Discrepancies between most of the known BSA formulae can reach 0.5m2 for the standard adult physique [3]. Although many previous studies have demonstrated that certain BSA formulae provide an almost exact fit with the patients examined, all of these studies have been performed on a limited and isolated group of people. 25 BSA formulae were analyzed to reveal that the choice of a particular formula is a difficult task. Differences among calculations made by the formulae are so great that, in certain cases, they may considerably affect patients’ mortality, especially for people with an abnormal physique or for children.
This problem is also apparent in the treatment of dogs. The dose of most cancer chemotherapeutic drugs administered to dogs is calculated on the basis of estimated BSA, yet some chemotherapy trials have revealed that this dosing method increases toxicosis in small dogs [4]. The current formula used to estimate BSA in dogs may be inaccurate or the assumption that BSA correlates with chemotherapeutic drug exposure may be unfounded.
Results suggest that the relationship between BSA and the physiologic and pharmacologic factors that influence drug exposure may not be closely correlated. Further studies are warranted to determine dosing methods that normalize chemotherapeutic drug toxicity in dogs. The effects of BSA on the pharmacokinetics of anti-cancer drugs have been studied retrospectively to find that in most cases, use of BSA does not reduce the inter-individual variation in the pharmacokinetics of adults [5]. As such, the rationale for further use of this tool in dosing adults is lacking.
Alternative dosing strategies have been proposed in order to replace the BSA-based dosing. Flat-fixed dosing regimens have been suggested that do not typically lead to greater pharmacokinetic variability, the implementation of genotyping and phenotyping strategies, and therapeutic drug monitoring, may probably be of more clinical value. In the end, the non-scientifically based BSA-based dosing strategy should be replaced by alternative strategies.
Despite the lack of basic fundamentals, BSA-based dosing still seems “untouchable” in clinical oncology. Consequently, the use of BSA in determining the dosage of medications with a narrow therapeutic index, such as chemotherapy, does not enhance to the concept of personalized medicine.
Drug Clearance
Drug clearance between individuals can vary by 4-10 folds due to differing drug elimination processes related to genetic and environmental factors [6]. Overdosing is easily recognized but it is possible that unrecognized under dosing is more common and may occur in 30% or more of patients receiving standard regimens. Those patients who are under dosed are at risk of a significantly reduced anticancer effect, there being an almost 20% relative reduction in survival for women receiving adjuvant chemotherapy for breast cancer and up to 10% for cisplatin-based chemotherapy for advanced testicular cancer.
The Area under the Curve (AUC), shown below, gives the integrated dose for concentration (y axis) vs. time (x axis). The shape of this curve f(x) depends on many factors but it is the concentration in the target tissue that gives the therapeutic effect. The integrated dose over time provides the average effect and cannot be less than the dilution of the hydrophilic drug in the Total Body Water (TBW) (Figure 1).
Figure 1: A specific AUC example is the Calvert (1989) [7] formula for carboplatin dosing where: Dose (mg) = (target AUC) x (GFR + 25) Where AUC = target area under the concentration versus time curve in mg/mL•min and Glomerular Filtration Rate (GFR) is measured by 51Cr-EDTA clearance.
Pre-treatment platelet count and performance status are important prognostic factors for severity of myelo-suppression in previously treated patients. Dose adjustments for single agent or combination therapy are modified from controlled trials in previously treated and untreated patients with ovarian carcinoma. Recommendations are based on the lowest post-treatment platelet or neutrophil value. AUC-based carboplatin dosing was found to be more accurate than dosing based on BSA.
Strategies using clinical parameters, genotype and phenotype markers, and therapeutic drug monitoring, all have potential and each has a role for specific drugs. However, no one method is a practical dose calculation strategy for many drugs. A potential and pragmatic system for initial dose calculation uses dose clusters and structured subsequent dose revision based on treatment-related toxicities and therapeutic drug monitoring. However, these models need to be tested in clinical trials [8].
Current practice is to put an upper limit on BSA for obese patients. Another approach is to rein the dose following adverse events in early treatments. While effective, these procedures admit to profound deficiencies in dose personalization.
Obesity
Both direct and indirect methodologies have been utilized to assess body composition [9]. Commonly used direct measures include underwater weighing, skin fold measurement and bioelectrical impedance analysis and dual-energy x-ray absorptiometry. A number of indirect measures have been developed such as height, bodyweight and sex, and include Body Mass Index (BMI), Body Surface Area (BSA), Ideal Body Weight (IBW), percent IBW, adjusted body weight, Lean Body Weight (LBW) and Predicted Normal Weight (PNWT).
The V(d) of a drug is dependent upon its physiochemical properties, the degree of plasma protein binding and tissue blood flow. Drug Clearance (CL) is the primary determinant to consider when designing a maintenance dose regimen and is largely controlled by hepatic and renal physiology. In the obese, increases in cytochrome P450 2E1 activity and phase II conjugation activity have been observed. However, the effects of obesity on renal tubular secretion, tubular reabsorption, and glomerular filtration have not been fully elucidated. The elimination half-life (t1/2) of a drug depends on both the V(d) and CL. Since the V(d) and CL are biologically independent entities, changes in the t1/2 of a drug in obese individuals can reflect changes in the V(d), the CL, or both. Pharmacokinetic data in obese patients do not exist for the majority of drugs. In situations where such information is available, clinicians should design treatment regimens that account for any significant differences in the CL and V(d) in the obese. As with the V(d), a single, well validated size metric to characterize drug CL in the obese does not currently exist. Dosages based on pharmacokinetic data obtained in normalweight individuals could induce errors in the drug prescription for obese patients [10].
Most of the pharmacokinetic information concerning obesity deals with distribution. Drugs with moderate to weak lipophilicity are homogeneous. In obese individuals, the total volume of distribution (Vd) is moderately increased or similar for most drugs, but the Vd per kilogram of bodyweight is significantly smaller. These drugs distribute to a limited extent in excess bodyweight.
For highly lipophilic drugs (cyclosporin, propranolol), Vd and Vd/kg are decreased suggesting that factors other than lipid solubility intervene in tissue distribution. For drugs with distribution restricted to lean tissues, the loading dose should be based on the ideal bodyweight of patients. For drugs markedly distributed into fat tissue the loading dose is based on total bodyweight. Adjustment of the maintenance dose depends on possible changes in clearance. These recommendations do not include BSA, but emphasize ideal (for hydrophilic) and actual (for lipophilic) body weight. The BF compartment includes all membranes and adipose tissue and determines the ultimate dilution of lipophilic drugs, the actual concentrations being determined as above. However, BF could well be a superior normalisation parameter to those listed above.
Hydrophilic and lipophilic drugs and total body water
Clinical response to chemotherapy often ranges from none to complete remission (often temporary). It is therefore difficult to determine the optimum dose; instead the median value from a range of body shapes in a clinical trial would be used. Most drugs are hydrophilic and dissolve in water to form a solution, the efficacy of which is governed by its concentration in the critical tissue. Too low a concentration and the drug is ineffective, too high and it’s toxic. The use of dose determination based on BM or BSA has long been shown to be inadequate in body composition studies [11-13], but is still used by Oncologists.
Fat is not a relevant factor for a water soluble drug, so the Total Body Water (TBW) should be used as the preferred starting point for dose normalization of hydrophilic drugs as this gives the overall drug concentration, which is the primary dose parameter. Cytotoxic drug elimination should be measured over time as the peak concentration could be more important that the integrated dose, but this is not practical in a patient management protocol.
Total Body Water
TBW can be measured directly using, for example, the protocol developed by Blagojevic and Allen (1989,1990) [14,15]. This is a laboratory protocol that requires heavy water for dilution, which is not readily available. However, a much more practical method is to determine the Fat Free Mass (FFM). The FFM excludes the fat compartment but includes Total Body Protein (TBP), Bone (TBB) and Water (TBW). Bone mass is fixed, protein varies slowly but water can change daily by hydration or elimination.
Consequently, the FFM gives the best indirect estimate of TBW, which relates to the efficacy of a drug in the target tissue. A simple example of the use of FFM in determining the personalized dose is given on the basis that the recommended dose is 1 unit of drug/kg BM. The “standard man” weighs 70kg, which may be the median bodyweight in a phase 1 clinical trial. The dose given would then be 70 units. However, for 20% body fat, the FFM would be 70-14 = 56kg. For a thin person with the same bwt and 10% fat, the FFM = 70-7 = 63kg. For a fat person with 30% fat, it would be 70-21 = 49kg. The hydrophilic drug doses for the 70kg man with different fat masses are given in Table 1.
Table 1: Normalised hydrophilic drug doses.
Assuming that the average FM is 20% for the clinical trial dose determination, then the thin man will be under dosed by 11% and the fat man over dosed by 14% if FFM is not used to normalize dose (Table 1). While most patients will lie within this band, obese or cachectic patients will be severely under or over dosed. It is therefore essential that FM be measured first to determine the optimal dose. The lipophilic drug doses for the 70kg man with different fat masses are given in Table 2.
Table 2: Normalised lipophilic drug doses.
Measurements
Body composition measurement with Dual Energy X-Ray Absorptiometry (DEXA) is used increasingly for a variety of clinical and research applications. DEXA total body scans give accurate and precise measurements of body composition, including Bone Mineral Content (BMC), Bone Mineral Density (BMD), lean tissue mass, fat tissue mass and fractional contribution of fat [16].
The scans are fast, simple, non-invasive with insignificant x-ray exposure. However, the role of DEXA in clinical evaluations and research studies has errors that are still of concern. DEXA may not be readily available in the Oncology setting. However, BF can be readily measured with adequate accuracy by measuring the thickness of subcutaneous fat in multiple places on the body with a Vernier caliper [17,18].
This includes the abdominal area, the sub scapular region, arms, buttocks and thighs. These measurements are then used to estimate total body fat. The equations predict body fat within 3-5% of the value obtained from underwater weighing but only if the person is of similar age, gender, state of training, fatness and culture to the population from which the equations were originally derived. With this qualification, the sum of skin folds is an entirely practical, very low cost protocol for patient management and dose normalization.
The point of this analysis is that the current BSA or BM protocols only apply to near standard patients. Typically, dosage is changed by the Oncologist on the basis of patient needs and clinical response. However, an Oncologist using the more appropriate FFM method could find that such adjustments would be reduced, although the management might be outside the current guidelines [19].
Although accepted for a century, the body surface area for patient dose determination has been shown to be inadequate. Phase 1 clinical trials should generate FFM data, which can then be used for patient dose normalization. This data can be readily obtained in any clinical trial, which then allows for obese or cachectic patients. Such trials could also incorporate direct measurement of TBW as well as FFM. Personalized patient therapy clearly requires improved normalization from clinical trial data in order to optimize the therapeutic response with minimal adverse events. The FFM method is expected to provide a much more suitable starting point for patient dose determination than BSA or BM. As such, the FFM should be specified in all phase 1 clinical trials. Only then can the FFM protocol be tested against the “standard” BSA method.
Allen BJ. Dose Determination for Hydrophilic and Lipophilic Drugs for Chemotherapy and Immunotherapy. SM J Clin Med. 2018; 4(1): 1032s2.
The purpose of this statement is none other than to highlight the importance of ethical standards and quality required in basic and applied research currently being done so we can subsequently inform health care professionals of new developments that are taking place in this area.
Ma. Esperanza Rodríguez-van Lier*
Chemotherapy is commonly used in cancer treatment. So far, chemotherapy agents can be categorized into three types: classical chemotherapeutic drugs, molecular target agents and cellular machineries target drugs.
Ziyou Wang1,2 and Zunnan Huang1,2*
Blood transfusion can cause some transfusion adverse reactions. In order to understand the incidence of adverse transfusion reactions, we performed a meta-analysis in Chinese hospitals. Of 809 literatures, seven studies involving a total of 211, 050 patients with blood transfusion treatment were included in this meta-analysis. Meta-analysis showed that the total incidence of adverse reactions was 0.4% [95% CI (0.2, 0.9), P < 0.0001]. Further subgroup analysis showed that the incidence of febrile and allergic reactions was 0.2% [95% CI (0.1, 0.5), P < 0.0001] and 0.2% [95% CI (0.1, 0.3), P < 0.0001], respectively. The common blood components caused adverse reactions were red blood cell, plasama, and platelet in clinical practice.
Yulu Gao1 , Qinyun Li2 , Zongshuai Gao2 , Yunxia Zhu4 , Yanqiu Liao5 , Changtai Zhu2 *# , Yongning Sun3 *#
Background: CT scanning remains one of the most routinely used diagnostic tools in a setting of Interstitial Lung Disease (ILD). New and improved technologies, such as High Resolution Computer Tomography (HRCT) have revolutionized the quality of imaging, leading to a prominent increase in number of incidental findings that may or may not be of any clinical significance. The aim of this study was to evaluate the prevalence of incidental findings on thoracic CT and their clinical significance.
Methods: Retrospective analysis was conducted on a cohort of 84 patients referred to our academic center as cases of ILD. Patients were referred for further evaluation between January 2000 and January 2014 and were followed over the disease course. CT scans were done annually as part of clinical management and patients were screened for any incidental findings. All incidental findings were reviewed, recorded in a clinical database and followed up on subsequent visits.
Results: 25 (30%) patients were found to have incidental findings. Liver abnormalities were found in 12 (14.29 %) patients. 11(13.10 %) patients were reported to have coronary artery calcifications. 5 (5.95 %) and 3 (3.57%) patients had thyroid abnormalities and renal cysts, respectively. A malignant lesion was found in 1 patient each in liver and thyroid abnormality subgroup.
Conclusion: Incidental findings are common on thoracic CT scans providing valuable and unexpected findings which warrant investigation by health care providers to exclude malignant processes.
Sonu Sahni1,2*, Sameer Verma1,2, Reeju S Thomas1 , Barbara Capozzi3 and Arunabh Talwar1,2
Hepatitis C Virus infection (HCV) is an increasing public health concern with an estimated 184 million people infected worldwide and approximately 350.000 yearly deaths from HCV-related complications.
Nesrine Gamal and Pietro Andreone*
We report a case of large cell undifferentiated lung carcinoma in a middle aged patient with previously treated tuberculosis and scarring. 20 pack years of smoking history was noted. He presented with metastasis at multiple sites including trochanter, liver and acute bilateral lateral rectus palsy. Chest radiography showed fibrosis of right upper zone with homogenous opacity. Sputum examination for AFB was negative. Computerized tomography of the thorax showed an irregular heterogeneously enhancing mass involving right upper lobe with cavitation, necrosis along with lymph node involvement and the erosion of the 4th rib with liver metastasis. Radiography of hip joint was suggestive of lesser trochanteric metastasis. MRI brain was suggestive of mass at base of brain in parasellar area. Fine needle aspiration cytology and CT guided biopsy confirmed undifferentiated large cell carcinoma of lung. Tuberculosis and smoking may increase the risk of lung scarring and malignancy and pulmonary scarring may be associated with increased lung carcinoma in ipsilateral lung. Clinician needs to be more sensitive to look for malignancy association particularly in patient with or previously treated for tuberculosis and even more emphasis to be laid if scarring of lung is observed.
Sreenivasa Rao Sudulagunta1 *, Shyamala Krishnaswamy Kothandapani2 , Mahesh Babu Sodalagunta3 , Hadi Khorram2 , Mona Sepehrar4 and Zahra Noroozpour1
Systemic Sclerosis (SSc) is a connective tissue disease characterized by fibrosis of the skin and internal organs, pronounced alterations in the microvasculature and frequent cellular and humoral immunity abnormalities. The rheumatic involvement of SSc is polymorphic and can reveal the disease or may appear during the course of its progression. Musculoskeletal involvement is dominated by non specific arthralgia, polyarthritis, and bony resorption especially acro-osteolysis. The diagnosis of these rheumatic manifestations is generally based on x rays examination. Musculoskeletal involvement in SSc is generally relieved with Non Steroidal Anti-Inflammatory Drugs (NSAID) or low dose of corticotherapy. The immunosuppressive therapy is used in corticoid-resistant or corticoid-dependent forms such us méthotrexate. The aim of our review is to presents an overview of the different osteoarticular and muscular involvement in SSc, their diagnosis and management.
Nessrine Akasbi*, Fatima Ezzahra Abourazzak and Taoufik Harzy
Sedigheh Mirhashemi1 , Mohammad Hosein Kalantar Motamedi1 *, Amir Hossein Mirhashemi2 and Hamid Reza Rasouli1
We encountered two autopsy cases of huge cardiomegaly with over 1000g in weight. Histochemical characteristics were examined using conventional staining including HE and Azan stains and immunohistochemical staining using antibodies against Complement Component 9 (CC9), RNA Binding Protein Motif 3(RBM3), Endothelial Type NO Synthase (eNOS) and Hypoxic Inducible Factor1α (HIF1). The reactive area with anti CC9 antibody, which presumed to be a marker of hypoxic change of myocardium, overlapped with eosinophilic area by HE and basophilic one by Azan. Although the reactive area with anti CC9 antibody showed relatively weak in the cytoplasm by anti eNOS antibody and no in the nucleus of cardiocytes with anti RBM3 antibody, outside of the reactive area with anti CC9 antibody there were intensive reactivity with anti eNOS antibody in cytoplasm and in a nucleus with anti RBM3 antibody. Anti HIF1 antibody showed weak reactivity with cytoplasm of endocardial cardiocytes and no with cytoplasm of cardiocytes in another area. The results obtained from the present cases revealed that the hypoxic change was equivalent even though the cause of cardiomegaly was deferred between two cases, and conventional staining such as HE and Azan utilized to detect hypoxic change in the heart and immunohistochemical studies seemed to be a useful tool for clarifying the cascade of hypoxic changes in the myocardium.
Satoshi Furukawa1,2*, Mayumi Kataoka1 , Satomu Morita1,2, Akari Uno2 , Masahito Hitosugi2 , Hiroshi Matsumoto1,3 and Katsuji Nishi1,2
A 45-year-old woman with multiple sclerosis was admitted to our hospital after out of hospital cardio-pulmonary resuscitation. The first ECG showed ventricular fibrillation. Following direct current defibrillation and mechanical reanimation, spontaneous circulation was restored and the ECG unremarkable without any signs of ischemia. Coronary angiography showed unobstructed coronary arteries Figure 1, (Panel A). Left ventriculography revealed apical wall obstruction, suggestive of apical aneurysm (Panel B, supplementary videos). Transthoracic echocardiography and Cardiac Magnetic Resonance Imaging (CMR) eventually lead to the diagnosis of a rare case of Apical Hypertrophic Cardiomyopathy (AHC) with ace of spades-form (Panel C,D). The patient underwent Cardioverter-Defibrillator Implantation (ICD) and amiodarone medical therapy for secondary prophylaxis. Patient’s family history and screening for HCM were unsuspicious.
Wiedemann S# *, Heidrich FM# , Speiser U and Strasser RH