Original Paper

Current Health Sciences Journal

Supplement 3, 2015

Original Paper CLINICAL PHARMACOKINETICS AND BIOPHARMACEUTICAL DATA APPLIED IN INDIVIDUALIZATION OF TREATMENT WITH TAMOXIFEN NAGWA IBRAHIM1, VALENTINA ANUTA2, I. MIRCIOIU3, IONELA BELU4 1

3

UMF Carol Davila, Faculty of Pharmacy, Bucharest, Romania

1

”Carol Davila” University of Medicine and Pharmacy, Faculty of Pharmacy, Department of Physical Chemistry, Bucharest, Romania

2

”Carol Davila” University of Medicine and Pharmacy, Faculty of Pharmacy, Doctoral School, Bucharest, Romania

”Ovidius” University, Faculty of Pharmacy, Department of Biopharmacy, Constanţa, Romania 4

University of Medicine and Pharmacy Craiova, Faculty of Pharmacy, Department of Pharmaceutical Technology, Craiova Romania

ABSTRACT: Tamoxifen is a selective estrogen receptor antagonist approved since 1970s for treatment and prevention of hormone receptors positive breast cancer. It has been proven to reduce disease recurrence by 50% and mortality by 30%. The limited use of tamoxifen for patients with estrogen receptor positive tumors presaged the era of personalized therapy for around 30 years. It has been reported that the response to tamoxifen has a high degree of inter-individual variability. Tamoxifen is a prodrug that needs to be metabolized to its active metabolite endoxifen by cytochrome CYP2D6. The allelic variations in CYP2D6 are determinant of tamoxifen treatment outcome, resistance and toxicity. The mechanism of variable response to tamoxifen and the potential association between genetic polymorphisms of CYP2D6 and tamoxifen clinical pharmacokinetics and clinical outcomes has been subject of interest. Scientists identified over 80 different CYP2D6 alleles and their frequencies variation among ethnic groups. Patients can be classified based on allele combinations or duplication into four major genotypes: poor metabolizers presents (homozygous for null alleles), intermediate metabolizers (heterozygous for null or partially functional alleles), extensive metabolizers (homozygous for wild-type alleles), and ultrarapid metabolizers (carrying more than two CYP2D6 copies in their genome). The reported data suggest that polymorphisms in CYP2D6 and estrogen receptors genotype might be useful in selecting women who would gain the highest benefit from tamoxifen and those who are susceptible to adverse effects and drug resistance. But due to contradictory results, implementation of tamoxifen genotyping in clinical practice is still debatable. On other hand, whatever the metabolizer type and estrogen receptors, the effect can be highly variable due mainly to biopharmaceutical characteristics of drug formulation, aspect practically neglected until now. Results of authors concerning variability of release kinetics and pharmacokinetics of tamoxifen determined by its low solubility and high lipophilicity are presented as possible starting points in further research for personalization of treatment.

KEY WORDS: Tamoxifen, genetic polymorphism, cytochromeP-450

Introduction Pharmacist’s traditional responsibilities were known as dispensing of pharmaceutics and compounding. Don Brodie is a pharmacist which received his baccalaureate in pharmacy 1943 and credited as the theoretician behind the shift of pharmacy’s focus from the product to the patient. In 1973 he posed the critical question of whether pharmaceutical education was prepared to lead the pharmacy profession [35]. He was the first introduced and defined the term pharmaceutical care [36]. He defined pharmaceutical care as “the care that a given patient requires and receives which assures safe and rational drug usage” [37]. Changing the

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focus of practice from products to patients ensure the best drug therapy and patient safety this will raise pharmacy’s level of responsibility and require different types of changes as philosophical, organizational, and functional. The American College of Clinical Pharmacy (ACCP) sets a strategic plan for the profession where pharmacists will be considered as accountable health care provider for optimal medication use and disease prevention. ACCP Board of Regents developed a definition of clinical pharmacy. A bridged definition is the area of pharmacy concerned with the science and practice of rational medication use. Unabridged definition is health science discipline in which pharmacists provide patient care that optimizes medication therapy and promotes health, wellness and disease


prevention [38]. Role of clinical pharmacists involve three major functions, identifying potential and actual medication related problem, resolving or preventing it medication related problems include untreated indications, improper drug selection, sub-therapeutic dosage, improper administration schedules etc. Tamoxifen is a hormone therapy belongs to the selective estrogen receptor modulators (SERMs). Individualization of treatment means tailoring drug selection, drug dosing, and route of administration and dosage form to a given patient based on the clinical situation. Currently drug individualization is the goal of clinical pharmacists, physicians and other health care professionals [39]. Oncology is a challenging field has continuous updates in cancer management strategies. Oncology requires multidisciplinary team involving oncologists, pharmacists, nurses, social workers, dietitians and spiritual therapist. Clinical pharmacists have a crucial role and can assist in with direct patient care and patient education activities. Currently there are more than 200 chemotherapy order templates oncology pharmacists led to develop. These templates dramatically decreased the time spend by oncologists writing chemotherapy orders and reduced the likelihood of prescribing errors as well. Tamoxifen is antineoplastic agent approved for treatment and prevention of hormone receptors positive breast cancer. It has been proven to reduce disease recurrence by 50% and mortality by 30%. It is also used as prophylactic treatment for women at high risk of developing breast cancer. Its standard of care therapy in premenopausal women is a 5 year treatment [37] but side effects can reduce quality of life and affect patient compliance [8]. Individualization of treatment starting from Physiological Based Pharmacokinetic (PBPK) data of tamoxifen, 4-OH tamoxifen, N-desmethyltamoxifen and endoxifen pharmacokinetics. It was hypothesized that interindividual variability might be related to altered pattern of tamoxifen metabolism. Jordan et al. introduced the theory about the link between tamoxifen clinical pharmacokinetics mainly metabolism and its response [9]. Tamoxifen is considered as a prodrug that needs to be metabolized to its active metabolite to be effective at the hormonal receptors sites. Bioconversion of tamoxifen to its potent metabolite endoxifen is primarily dependent on

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the activity of cytochrome CYP2D6 which is highly polymorphic. Many studies reported the potential association between CYP2D6 polymorphism and tamoxifen clinical outcome [10]. A detailed model-based analysis of the mass balance offered support for a further investigate the linkage of PK, mode of action, and treatment outcome independence of factors such as phenotype, ethnicity, or co-treatment with CYP2D6 inhibitors [42]. Tamoxifen is a substrate of cytochrome P450 3A, 2C9 and 2D6, and an inhibitor of Pglycoprotein. It is predominantly metabolized by the cytochrome P450 (CYP). Tamoxifen metabolism occurs mostly through two pathways, 4-hydroxylation and Ndemethylation. The 4-hydroxylation pathway is catalyzed mainly by CYP2D6, resulting in metabolite 4-hydroxy-tamoxifen. This pathway contributes around 7% of tamoxifen metabolism. N-demethylation pathway is catalyzed primarily by CYP3A4 and CYP3A5, resulting in metabolite N-desmethyltamoxifen. This pathway contributes around 92% of tamoxifen metabolism. N-desmethyltamoxifen is further metabolized to endoxifen via hydroxylation by CYP2D6. Endoxifen shown to be about 30 to 100 fold more potent as an estrogen receptors antagonist compared to tamoxifen. CYP2D6 plays a major role in the biotransformation of tamoxifen and many other drugs including antidepressants and selective serotonin reuptake inhibitors and blockers [10-13]. Each gene encodes for CYP450 enzymes has a known genetic polymorphisms that affect its catalytic activity. In case of tamoxifen single nucleotide polymorphism in CYP2D6 genes can lead to complete lack of enzymatic activity due to the formation of truncated inactive proteins. CYP2D6 is responsible for the hydroxylation of N-desmethyl tamoxifen to endoxifen. Variation in individual therapeutic benefit from tamoxifen might be affected by the genetic variations that cause differences in CYP2D6 metabolizer status [11-19]. Patients can be classified based on allele combinations or duplication into four major genotypes: Poor metabolizers presents (homozygous for null alleles), intermediate metabolizers (heterozygous for null or partially functional alleles), extensive metabolizers (homozygous for wildtype alleles), and ultrarapid metabolizers (carrying more than two CYP2D6 copies in their genome) [20-25].

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Effect of CYP2D6 inhibitors. The enzymatic activities of CYP2D6 can be affected not only by the presence of various polymorphisms but also due to intake of many drugs. Examples for strong CYP2D6 inhibitors are fluoxetine, paroxetine and quinidine. Examples for moderate inhibitors are steraline, duloxetine, diphenhydramine, cimetidine and amiodarone. Other drug interactions can be found at www.drug-interactions.com. The question of whether or not cytochrome P450-2D6 (CYP2D6) polymorphisms significantly affect treatment outcome still remains controversially discussed [52,53]. Genomic clinical pharmacokinetics in individualization of treatment with tamoxifen. The mechanism of variable response to tamoxifen and the potential association between genetic polymorphisms of CYP2D6 and tamoxifen clinical pharmacokinetics and clinical outcomes has been subject of interest. Many outstanding researches have been published methods for reducement of of this variability. Hyeong-Seok Lim and colleagues assessed the association between genetic polymorphisms of CYP2D6 and PXR, and tamoxifen pharmacokinetics and clinical outcomes in patients diagnosed with breast cancer. Results revealed that CYP2D6*10/*10 is associated with lower steady state plasma concentration of tamoxifen active metabolite. This conclusion might possibly influence the tamoxifen clinical outcome in Asian breast cancer patients [26]. Rob der Heine and colleagues assessed the impact of CYP2D6 and CYP3A metabolic phenotypes on the pharmacokinetics of tamoxifen and endoxifen. They concluded that both CYP2D6 and CYP3A metabolic phenotypes explain the variability in edoxifen formation. The interindividual variability reduced from 55% to 25% [27]. Hot flashes are a common side effect for tamoxifen. It is usually treated by paroxetine. Vered Stearns and colleagues tested the effect of coadministration of tamoxifen and the selective serotonin reuptake inhibitor (SSRI) paroxetine, an inhibitor of CYP2D6, on tamoxifen metabolism. Results revealed that coadministration of paroxetine and tamoxifen decrease the plasma concentration of endoxifen. They suggested that CYP2D6 genotype and drug interactions should be considered in women treated with tamoxifen [28]. Timothy L. Lash and colleagues conducted a large case control study nested in the population of 11251 women at diagnosis of stage I-III

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breast cancer. They estimated the odds ratio associating CYP2D6 inhibition with breast cancer recurrence and adjusted for potential confounding with logistic regression. They concluded that the association between CYP2D6 inhibition and recurrence in tamoxifen treated patients is likely null or small [29]. Werner Schroth and colleagues investigated the role of CYP2D6 variants in the outcome of adjuvant tamoxifen therapy by poor metabolizer and intermediate metabolizer approach. Also they analyzed CYP3A5, CYP2B6, CYP2C9 and CYP2C19 variants being contributed in the formation of the active metabolite. They concluded that genotyping for CYP2D6 alleles *4, *5, *10 and *41 can identify patients who will have little benefit from tamoxifen in the adjuvant settings. Also they reported that the CYP2C19 *17 in addition to functional CYP2D6 alleles identifies patients possibly to benefit from tamoxifen [30]. Matthew P. Goetz and colleagues determined the relationship between CYP2D6 *4, *6 and CYP3A5 *5 genotype and disease outcome. Results revealed that patients with the CYP2D6 *4/*4 genotype are at higher risk of disease relapse and have lower incidence of hot flashes [31]. Kazuma Kiyotani and colleagues investigated the relationships of polymorphisms in transporter genes and CYP2D6 to clinical outcome of patients receiving tamoxifen. They concluded that CYP2D6 variants were significantly associated with shorter recurrence free survival in patients with two variant alleles versus patients without variant alleles. The number of risk alleles of CYP2D6 and ABCC2 showed cumulative effects on recurrence free survival. Patients carrying four risk alleles had 45.25 fold higher risks compared with patients with≤one risk allele. CYP2D6 variants were associated with lower plasma levels of endoxifen and 4 hydroxytamoxifen [32]. Another promising study conducted by Tomoko Ota and colleagues. They developed a new straightforward TaqMan PCR genotyping assay to investigate the prevalence of the most common allelic variants of polymorphic CYP enzymes CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A5 in the Japanese population. The genotype analysis identified a total of 139 out of 483 genotype combination of five genes in the 1003 Japanese subjects. Accordingly it seems most of the subjects require dose modifications during clinical treatment. They expected that in the near future,


dose modifications should be considered based on the individual genotype [33]. An excellent review was done by Timothly L. Lash and colleagues. They discussed the published data about evidence and practice regarding the role for CYP2D6 inhibition and decision about tamoxifen therapy. They commented about the presence of published incomplete biologic evidence and inconsistent epidemiologic evidence and how should clinical oncologists counsel patients about the potential for CYP2D6 inhibition of tamoxifen effectiveness? The absence of consensus guidelines that might be related to the published contradictory results and uncertainty that led to hesitation whether one should apply tamoxifen genotyping in clinical practice given the current evidence? The current knowledge about endocrine therapy treatment individualization for breast cancer patients represents the tip of the iceberg and reveals a bit more of what lies below the surface [34]. We can notice from the published studies the limitation in the evidence that led to hesitation about using CYP2D6 genotyping as a routine in clinical practice. There are contradictory results related to the impact of CYP2D6 on tamoxifen treatment outcome. Some of the study results were positive and others were negative. There is no single factor can consistently differentiate positive results from negative results. Implementation of genotyping is still debatable for several years. We still waiting reliable evidence from well designed clinical trials. Biopharmaceutic and pharmacokinetic approach of variability in tamoxifen PK Pharmacokinetic issued incertitudes. Tamoxifen is available as 10 mg tablet and administered as 20mg once daily. The average peak plasma concentration of a range of 35 to 45ng/ml occurs about 5 hours after administration of 20 mg single oral dose. The reduction in tamoxifen plasma concentration is biphasic with a terminal half life of about 5-7 days. The steady state concentrations of tamoxifen are achieved in about 4 weeks after initiation of therapy and the steady state concentrations for N-desmethyl tamoxifen are achieved in about 8 weeks. The suggested half life for the metabolite is 14 days [1,2]. Considering for simplicity a monocompartmental model and 7 days as halftime, the elimination constant will result

= ke

ln 2 = 0.1 days −1 7days

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and fraction remained in the body at the end of one day will be An elementary calculus which can be found in all pharmacokinetics standard books leads to conclusion that, at steady state the plasma levels −0.1 will reach a values= 0.9 times greater q e= than after the first administration which results have to be more in depth analyzed. So that, when is possible, measuring of plasma levels at equilibrium is important for avoiding uncontrolled increasing of adverse effects. Biopharmaceutic issued incertitudes. Dosage forms possess poor solubility and poor dissolution rate are major obstacles for improvement of pharmaceutical formulations. These drugs possess low absorption rate and bioavailability as well. Solubility is a determinant for drug liberation which is a key role in its bioavailability. Solubility is affected by different key factors as the medium pH, cosolvents, temperature, surfactants, pressure, solute concentration, solute molecular structure, complex formation and salting out, while oral bioavailability depends on several factors as aqueous solubility, drug permeability, dissolution rate and first-pass metabolism [43]. Pharmacy is the key profession dealing with improvement of oral dosage form solubility and drug delivery. Pharmacists are the expert in drug development. They have the background of pharmaceutical science essential for productions of drugs possess good solubility characteristics and high bioavailability which are essential for better efficacy and better clinical outcome. This will lead to treatment individualization, high patient compliance, and cost effectiveness. Physicochemical properties inducing variability of in vivo release and absorption. Dissolution testing is initially developed for solid oral dosages form both for immediate release or extended release. Recently, it is winded to other dosage forms as suspensions, chewable tablets and transdermal patches. There is a significant difference in formulation design of these dosage forms. In turn, this will lead to very different physicochemical and drug release characteristics. Dissolution testing is used in phases for product release development and stability testing. It is used to detect physical changes in formulated product. To characterize the drug release from the dosage form adequately we must determine the release (dissolution) values as a function of time. Certain factors should be considered while developing in vitro dissolution/release test for a dosage form such as relevant bioavailability,

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clinical data, and the physiological conditions at the site of administration. The complexity of the dosage form release mechanism and lack of knowledge about the in vivo conditions under which drug release occur might make it hard to develop and design physiologically based tests. Dissolution process means extracting the active pharmaceutical ingredients from the solid dosage form into the gastrointestinal tract solution. It is an in vitro process indicates the efficiency of in vivo dissolution [39]. In vitro and in vivo correlation is a tool used to predict in vivo results based on in vitro results. It is often used to reduce development time and to optimize the formulations. In vivo data is obtained from well designed and standardized studies on human [41]. Chemically, tamoxifen citrate is the transisomer of a triphenylethylene derivative, and is formulated in oral pharmaceutical products as a tamoxifen:citric acid 1:1 complex (Figure 1).

Figure 1. Tamoxifen Citrate chemical structure

Tamoxifen is a weak base, therefore ionization will occur in the gastric environment, leading to a predicted rapid dissolution in the stomach. As the drug is emptying from the stomach to the duodenum, the degree of ionization is significantly reduced due to the elevated pH, with possible precipitation of the drug [44]. Lipophilicity. Its high lypophilicity (logP=5.93) [46] makes the presence a foodeffect highly probable. This leads to a complicated intestinal absorption model, controlled by many factors, including the extent of supersaturation, pH, fluid volume, viscosity, and bile salts concentration, therefore biorelevant simulation of gastrointestinal conditions is essential to adequately predict its in vivo behaviour. Tamoxifen belongs to BCS Class II (high permeablility, low solubility) [45] providing dissolution rate-limited absorption.

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Poor water solubility. Very few research works carried out to improve solubility of tamoxifen. As the drug is emptying from the stomach to the duodenum, the degree of ionization is significantly reduced due to the elevated pH, with possible precipitation of the drug [44]. Experimental approaches regarding release kinetics and in vitro-in vivo correlations As part of a drive to obtain predictive in vitro models to forecast the in vivo performance of tamoxifen, biorelevant dissolution media simulating conditions in the proximal small intestine, Fasted-State Simulated Intestinal Fluid (FaSSIF) and Fed-State Simulated Intestinal Fluid (FeSSIF), were developed [47]. Compendial dissolution media for comparative approach consisted in the followings [48]: simulated Gastric Fluid (SGF) pH 1.2 buffer and simulated Intestinal Fluid (SIF) pH 6.8 buffer. A set of four biorelevant media was used, proved to be representative for the fasted stomach (FaSSGF), the postprandial stomach (FeSSGF), fasting state conditions in the small intestine (FaSSIF) and simulated postprandial conditions in the small intestine, (FeSSIF). The release kinetics of Tamoxifen was strongly dependent on the composition of release media, critical factors being apparently the pH and concentration of physiological surface active agents. Results suggested that effect of bile salts is in all cases greater than the effect of pH. Correlation of in vivo results with dissolution tests is likely to be best for those drugs, because in this case the dissolution rate is the primary limiting aspect to their absorption. [49-51].

Conclusion Based on the available evidence, there is uncertainty about considering genotypes as a biomarker to predict the tamoxifen treatment clinical outcome in breast cancer patients. Results from recent studies reveal a bit more from the hidden knowledge about this important topic. There is a lot of promising data about genotype-guided tamoxifen therapy to improve the potential of personalized treatment, but its routine use is not yet recommended. It is wise to wait more reliable evidence from well designed clinical trials. Pharmacokinetic considerations connected to repeated doses of tamoxifen have to be taken into consideration for avoiding risk of accumulation in plasma and exacerbations of adverse effects.


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