Introduction

Recently, the role of gender as a factor in drug pharmacokinetics and pharmacodynamics has become better appreciated [1]. Therefore, gender difference is a major area of interest within the field of drugs pharmacology. The usual weight difference between men and women can potentially influence body water spaces, muscle mass, organ blood flow, and organ function, and therefore, it could also affect pharmacokinetic parameters of many drugs, e.g., aliskirin, an antihypertensive rennin inhibitor, as well as fluconazole, an antifungal drug [2, 3]. Furthermore, women tend to have a higher percentage of body fat than men do which could affect the volume of distribution of lipophilic drugs [4] such as trazodone [5] and sufentanil [6], and many more. Women often exhibit a moderately faster clearance of drugs metabolized by the major metabolic CYP3A4 pathway [7] and also show alterations in the disposition of drugs in relation to the phase of the menstrual cycle [8], pregnancy [9], or after menopause [10].

Pharmacokinetic and pharmacodynamical changes can affect both the desired therapeutic effect of a drug as well as its adverse effect profile [11]. Assessment of pharmacodynamical differences between men and women requires the control of pharmacokinetic factors and should use the appropriate methodology to relate the response to a drug’s plasma and bio-phase concentrations [12]. There are many notable examples of marked gender differences in a drug’s effectiveness and efficacy. Aspirin is less effective in women in the prevention of stroke, which may be related to the gender hormone-dependent difference in platelets aggregation [13]. Pentazocaine, an opioid drug, shows greater efficacy for pain relief in women than in men, but ibuprofen exhibits a reverse response with no gender-associated differences in kinetics [14]. Corticosteroids drugs which are widely used for their anti-inflammatory and immunosuppressive properties also exhibit pharmacokinetics/pharmacodynamics which can be influenced by gender difference [12]. These findings suggest that gender-specific differences in body composition may result in variable drugs disposition and responsiveness.

Therefore, this paper provides a brief overview of the existing evidence for gender-specific differences in pharmacotherapy. This overview is organized along the following questions: (1) What is the fundamental difference between the male and female body composition? (2) What factors are responsible for a drug’s differential pharmacokinetics and pharmacodynamics? (3) Why it is the right time for gender-based pharmacotherapy? (4) What efforts are/research is needed to move forward? (5) What impact might gender based effect have for transforming the population’s health status? We systematically reviewed the data for gender-based differences in pharmacotherapy with the aim to provide a comprehensive review of this topic.

Method

This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [15].

Data sources

A comprehensive search of MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials and Database of Systematic Reviews from the earliest available online year of indexing up to May 2016 was conducted. We used the following text words as search terms “gender difference pharmacokinetics/pharmacodynamics”, “sex difference pharmacokinetics/pharmacodynamics”, “male and female pharmacokinetics/pharmacodynamics”, “gender effect of medication”, “male and female difference”, etc. Our search included articles published in English and non-English languages. We also scanned the bibliographies of all retrieved articles for additional relevant articles. Further, the authors of potentially eligible abstracts, posters, or manuscripts were contacted via e-mail to obtain additional data, if possible. However, we did not include any unpublished data in our analysis.

Study selection and eligible criteria

Two of our authors (Md. M.I. and P.-A.N.) independently performed article selection, data extraction, and assessment of risk of bias. All disagreements were resolved by consensus with our main investigators.

Studies were included if they met the following inclusion criteria: (1) Controlled observational and clinical studies, (2) studies reported cases of male and female dose difference; (3) studies which had more than 5 participants, and (4) p value <0.05, or sufficient data were available to calculate a p value.

We excluded studies if for the following reasons: (1) it was only a case report, an editorial, or a review; or (2) studies that did not provide a sufficient amount of information regarding gender-specific difference in the pharmacokinetics and pharmacodynamics outcome.

Data extraction

Twenty-six studies that fulfilled all of our criteria as stated above were then independently entered into our database by the two authors, with the following entries: first author’s last name, publication year, country source of study, participants’ characteristics, method of ascertainment of dose difference, sample size, variable adjustment, etc. We also screened the title, abstract, and full text in a similar fashion; however, specific exclusion reasons were documented only during full-text screening. Upon selection of the final group of studies, the same two authors independently extracted the qualitative and quantitative data using a standardized data extraction form adjudicated by a third author (S.-A.S)

Outcome parameters

The two primary outcome parameters of this systematic review were: (1) to address the factors for gender-specific differences in pharmacokinetics and pharmacodynamics; and (2) to identify the medications which should have different dosage recommendations for men and women.

Results

Study selection

The search strategy identified 18,183 articles. Of these, 18,032 articles were excluded based on our predetermined eligibility criteria described above, while the remaining 151 articles underwent detailed full-text evaluation. Among these, only 26 published articles met our inclusion criteria. The most common reason for exclusion of the 125 excluded studies was lack of participants (n = 55), followed by ineligible study design (n = 37), unable to locate full text (n = 12), full-text duplication (n = 4), and so on. Figure 1 summarizes our selection process.

Fig. 1
figure 1

Diagram of study selection, adapted from PRISMA group 2009 flow diagram

Full size image

Study characteristics

This systematic review identified 6309 subjects which were mentioned in 21 studies; we also included five further studies which did not mention any gender-specific information. Table 1 shows the general characteristics of these 26 observational or clinical studies which we included in the final systematic review. Four studies were clinical trials, and 22 studies were observational studies. These studies were published between 1990 and 2016, spanning 26 years. 14 studies were conducted in North America, eight studies in Asia, and four studies in Europe. All studies included a significant number of subjects ranging from 14 to 1005.

Table 1 Some studies related to pharmacokinetics and pharmacodynamics difference between male and female
Full size table

Systematic review:

We conducted a primary systematic analysis using the 26 studies which reported results on 26 different groups of drugs based on gender-specific difference effect. A qualitative synthesis of these 26 studies is shown in Table 1. 17 out of 26 studies reported that a higher plasma drugs concentration for women, even though the dose was similar [16–32], and the range of drug plasma concentration in women was 10–30% higher than in men. However, in some cases, the drug plasma concentration in women was greater than 80% when compared to that of men [21, 31, 32]. We also found a slower clearance rate [25, 33–38] and a lower volume of distribution [12, 20, 33] in women compared to men. Only one study mentioned a faster clearance rate for women [39].

To further elicit the factors that are responsible for altering drugs pharmacokinetics and pharmacodynamics, we divided the drugs into different groups. The commonly used drugs such as anti-malarials [16], anti-depressants [18, 22, 32], antibiotics [20, 33], bronchodilators [40], steroids [12, 41], antihypertensives [19, 23, 30, 31, 39], and anti-virals had a gender-specific effect. Examples included studies of steroidal drugs such as Rocuronium and Pancuronium, in which women were 30% more sensitive when compared to men. Women had a higher plasma drug concentration in various types of medication such as valproic acid [17], Desvenlafaxine [18], Carvedilol [19], Encenicline [21], Clomipramine [42], Amiodarone [23], Delavirdine [25, 43], oxcarbazepine and carbamazepine [44], Metoprolol [30], etc. Likewise, women had a lower volume of distribution for Methamphetamine [45], Levofloxacin [33], Albuterol [40], and Ofloxacin [20], and a slower rate of clearance for Verapamil [39], Parampanel [37], and Rosuvastatin [38, 46], etc.

Most of the studies indicated that women tend to have a lower body weight, a higher amount of body fat, lower plasma volume, and a metabolic rate which is higher for cytochrome P450 (CYP) 3A4 substrates, and a lower hepatic activity for the drug efflux transporter P-glycoprotein than men [12, 16, 19, 38, 39, 41, 42, 46]. In contrast to earlier findings, however, we also found that the digestion factor could modify the pharmacological action of the medication. Women are physiologically liable to produce less gastric acid than men because of their slower digestion of foods [19, 42]. Finally, the studies mentioned that the menstrual cycle and steroid hormones are also responsible for modifying a drug’s action [24, 27, 28, 34–36, 47].

Discussion

We obtained 26 studies which provide evidence about the factors which are mainly responsible for altering drugs pharmacokinetics and pharmacodynamics. We identified gender-specific differences for numerous molecular and physiological factors affecting the pharmacokinetics of therapeutic agents, and these pharmacokinetic differences might result in variation of the pharmacological response of men and women. Gender-specific differences in drug distribution might be expected because of the different proportions of muscular and adipose tissue in men and women [48]. The 26 studies overall agreed out that women usually have a lower body weight, shorter organ sizes, and lower plasma volume and blood flow, as well as a higher percentage of body fat. Table 2 shows the basic fundamental difference between men and women that could change the pharmacological action of drugs. However, the systemic exposure and the average concentration of drugs in a steady state depend on its clearance, difference in volume of distribution, and the resulting modification of half-life which are all relevant to the peak which is attained after administrating drugs.

Table 2 Different factors responsible to gender-specific drug effects
Full size table

There are several possible explanations for this effect. It is interesting to note that in all the 26 included studies, some female hormones may modify gastric acid secretion, and therefore, gastric PH can lead to slower gastric emptying time in women [49–51]. This could change the significant delay of the onset of an effectiveness of enteric-coated forms, and drugs solubility, as well as dissolution [52]. Table 3 shows the reason for gender-specific differences in drug absorption. However, women usually have a lower organ blood flow which diminishes the blood flow and may thus cause a slower rate and probability lower extent of drug absorption [53]. Higher plasma level is reached in women when compared to men in oral drugs such as ciprofloxacin, oxafloxacin, levofloxacin, gatifloxacin, etc. [54–58], but they also indicate that this difference disappears when the data are normalized by the body weight of an individual.

Table 3 Pharmacokinetics variation based on physiological characteristics between male and female
Full size table

The most obvious finding to emerge from our review is that the plasma volume, body mass index, average organ blood flow, total body water, and body fat difference between men and women also change the distribution as well as the entire pharmacokinetic process [1, 59–61]. Hydrophilic drugs such as atenolol [62] and ranitidine [63] tend to stay in the blood and the fluid which surrounds the cells [64]. Similarly, Arthur (1994) identified alcohol and ranitidine which revealed a smaller volume of distribution and produced a higher Cmax in women [65]. Other researchers mentioned that due to body fat variation, women have a higher plasma volume of distribution when they intake lipophilic drugs like benzodiazepine [66, 67]. This is because lipophilic drugs have an inclination to be concentrated in fatty tissues. Table 4 lists some drugs whose distribution rate varies between men and women.

Table 4 Examples of some drugs associated with gender difference in distribution
Full size table

Another possible explanation for this is that the drug’s metabolism was the primary focus to explain gender-specific differences in the pharmacokinetics of medicines [49]. For example, the activity of the enzyme pathway in men and women is different. Several enzymatic pathways are reduced in women, whereas, in other cases, the channels are increased in women. Table 5 shows different enzymatic pathways that play a crucial role in drug metabolism in response to gender factors. Tsutsumi et al. [68] described CYP1A which is more prevalent and led to genetic polymorphisms with the extensive metabolizer phenotype. Several studies analyzing metabolite ratios confirmed that men have a higher rate of clearance when caffeine is administered intravenously or orally [69–72]. Furthermore, gender-specific differences in clearance of CYP1A2 substrates were observed in the case of clozapine, olanzapine, and theophylline [49]. Increased levels of estrogen and progesterone alter hepatic enzyme activity, which can increase drug accumulation or decrease elimination of some drugs. Female steroid hormones and prolactin play a role in autoimmunity. However, metabolic changes can also depend on hormone levels that change during the menstrual cycle, with the use of oral contraceptives, throughout pregnancy, or during menopause. Although some researchers believe that the sex hormone plays a dominant role in modulating sex-based differences in pharmacokinetics, such a conclusion result is still controversial. Researchers have failed to show any difference in the case of caffeine [69], paracetamol [73], and ropinirole [74] during the menstrual cycle. Likewise, they did not find any sex-related or menstrual cycle-related differences when treating migraine patients with elitriptan [75].

Table 5 Gender difference metabolism and excretion of some drugs
Full size table

Therefore, it is important to consider gender-specific differences in pharmacotherapy, because a significant amount of studies mentioned that adverse drugs reaction is 50 to 70% more likely in women [76–80]. The overall incidence of suspected adverse drugs reaction in women was 20.6 per 10,000 patient-months of exposure, whereas in men, it was only 12.9 per 10,000 patient-months of exposure [78]. The most common adverse effect in women is neuropsychiatric, whereas rarer adverse effects are cardiovascular [81], gastrointestinal [82, 83], cutaneous allergic disturbance [83], blood dyscrasias [82], electrolyte disturbances [83], and urinary tract disorder [84]. The Spanish System of Pharmacovigilance reported that 60% of 1609 adverse reactions (OR = 1.67, 95% CI) were due to nonsteroidal anti-inflammatory drugs in women [79]. Moreover, in a review of 93 articles investigating cardiac drugs, 70% of women observed ADRs, even though it is thought there is a male predominance usage of antiarrhythmic drugs [80]. However, anti-infective (60.4%), nervous system agents (21.5%), and musculoskeletal agents (3.7%) reported higher number of ADRs in women [84, 85].

Gender-related dissimilarities in the pharmacokinetics and pharmacodynamics of these drugs have been considered as major determinants for the higher reporting of adverse drugs reactions in women. Likewise, Anderson et al. [52] reported that female patients always had a higher adverse effect of drugs as a consequence of their physiological difference. Several studies showed that female patients have a 1.5- to 1.7-fold greater risk of developing an adverse drug reaction [86, 87], and gender-related drug pharmacokinetics and pharmacodynamics variation play a crucial role in adverse effects [48, 84, 88] (Table 6 ). Much of the research up to now has described adverse effect which occurs due to the type of drugs, administration route, treatment duration, dosage, and bioavailability, but they always ignored gender-specific differences. The rate of adverse effect always varies with patient characteristics which include age, gender, ethnicity, coexisting disorders, and genetic or geographic factors [89–91].

Table 6 Reasonable factors for gender difference adverse drug reaction
Full size table

This combination of findings provides some support for the conceptual premise that it is necessary to adjust the dosage or even change medications by gender differentiation. When a patient differently responds to the same amount of dosage, it is recommended that the physician takes into consideration the patient’s sex when they make any decision regarding changing the dose or the medication. Physicians should prescribe medication after considering these differences to minimize the adverse effect and enhance therapeutic effectiveness. The complexity of the female body due to hormonal changes, the menstrual period, the use of birth control pills, and the menopause alters the pharmacological action of drugs due to variation in pharmacokinetics and pharmacodynamics. Nowadays, clinicians are becoming more aware of dissimilarities in the response to treatment of men and women [49, 92], but it is not yet satisfactory. For example, when doctors prescribe medications for pregnant women, particular attention should be paid to drugs treatment, because drugs respond differently during pregnancy [9, 93, 94].

Several questions remain unanswered at present. Since men and women are biologically different, increasing awareness of the possibility of gender on PK/PD variation could influence future clinical trial design. This will create many opportunities to understand the relevance of gender-specific effects, because they certainly do not exist for all drugs, because only 6–7% of those that include a pharmacokinetic gender analysis displaying significant gender differences [52]. It is important to examine whether men and women exhibit different basal expression profiles of drug metabolizing proteins in relevant tissues. Therefore, a human gene expression database is required. This would constitute a large undertaking involving tissues from organ donors and gene expression facilities on a large scale [95]. Moreover, for the issue which is related to non-growth hormone non-drug exposure mechanisms and related to drug metabolizing enzyme or transporter expression, drugs need to be examined on an individual basis.

Our systematic review has several limitations. We did not include race and ethnic factors for PK/PD difference despite racial difference in pharmacokinetics of several drugs having been demonstrated [96]. For example, methylprednisolone clearance was 50% higher in white patients than black patients in a gender- and age-matched study in renal transplants recipients [97]. Black patients were also found to have a different toxicity profile than white patients [98]. Finally, it is not possible to draw conclusions regarding causality through more retrospective observational studies. Therefore, the results of this study should be regarded with caution.

Conclusion

Our study discusses possible reasons for male and female dose differences. As the literature suggests, there are differences how the male and female body deal with drugs because of their differential physiological characteristics. In general, therefore, the current data highlight the importance of involving more females in clinical trials for better results. While the present study is based only on analyzing the published literature, the findings suggest that it may be necessary to differentially adjust the dose for men and women for their safety and efficient treatments. Our study will hopefully serve as a base for future studies and create a better awareness to healthcare providers regarding this issue.