Pharmacokinetic considerations in the use of anticancer drugs during pregnancy: challenges and new developments

Abstract

Cancer complicates approximately 0.1% of all pregnancies, and the incidence is expected to increase, as more women elect to defer child-bearing to a later age. For these women and the clinicians treating them, there is little rigorous evidence with which to guide their management, but thought must be given to the effects of chemotherapeutic agents on the developing fetus and the effects of physiological changes within the pregnant women. We examine the evidence available for the effects of cytotoxic chemotherapy on the development of the fetus and for the health of the child in the longer term, and the effects of transplacental transfer and physiological changes of pregnancy on the pharmacokinetics of these drugs. These factors may have significant influence on the appropriate dosing of chemotherapeutic agents in pregnant women, compared to their nonpregnant counterparts, and further research is required into the implications of these findings for the successful treatment of cancer in pregnancy.

Keywords:

• anthracyclines
• cancer
• chemotherapy
• pharmacokinetics
• pregnancy
• taxanes
• treatment

The incidence of cancer in pregnancy is relatively low: approximately 0.1% of all pregnancies [1,2]. However, increasing age is associated with increasing incidence of cancer, and the incidence of cancer in pregnancy is expected to rise in the coming years, as more women elect to defer child-bearing to a later age. Understandably, common cancers diagnosed in pregnancy are those commonest in women of child-bearing age: breast cancer, cervical cancer, Hodgkin and non-Hodgkin lymphoma, leukemia, ovarian cancer and melanoma [2].

For these women, and the clinicians treating them, there is little rigorous evidence with which to guide their decisions: no prospective randomized controlled trials exist and, hence, there are no good clinical guidelines; most evidence on the management of cancer in pregnancy comes from single case studies or small case series [3]. The management of pregnant women with cancer poses unique challenges, both because of the potential effects on the development of the fetus and because of physiological changes within the pregnant woman herself.

In managing cancer in pregnancy, there are three key considerations: First, the effect of any chemotherapy agents on the fetus, both in the immediate (gestational) period and in the longer term, including following delivery and throughout life. Second, although related to the first, is transplacental transfer of cytotoxic chemotherapy, which both increases the dose to the developing fetus and increases the volume of distribution for the drug, by including the fetal circulation. This is particularly the case for drugs that have a high proportion of transplacental transfer. Third, the physiological changes of pregnancy themselves have implications for the pharmacokinetics of chemotherapeutic agents, in their distribution, metabolism and elimination.

Cytotoxic chemotherapy agents are known to cause congenital developmental defects when given during the period of organogenesis in the first trimester [3,4], and it is therefore recommended that chemotherapy is deferred until the second or third trimester. While there is evidence that the administration of chemotherapy in the second and third trimesters is associated with fetal growth retardation and infants that are subsequently small for gestational age [3,4], evidence is lacking that this translates to increased morbidity or mortality for the child following birth. More recent evidence suggests that prematurity is of greater risk to the child than interuterine exposure to chemotherapy [5], and carrying the pregnancy as close to term as possible is a better strategy for the health of the child than early delivery, with no deleterious effect on the health of the pregnant woman or the efficacy of chemotherapy.

There are few studies looking at the effects of chemotherapy on children exposed during treatment for maternal cancer. Such studies that do exist [4,6-8] are reassuring, with no evidence of significant health or developmental problems in exposed children. However, it must be emphasized that these studies focused on relatively small populations and relied on parent- or guardian-reported outcomes, which are vulnerable to bias. Avilés et al. performed echocardiography on 81 children exposed to anthracyclines during gestation, but found no evidence of significant cardiac abnormality, with an average follow-up from birth to 29 years of age [9]. This lack of apparent cardiac toxicity could be explained by the low rate of transplacental transfer of these drugs.

Transplacental transfer of chemotherapeutic agents influences the volume of distribution of these drugs and the volume of drug delivered to the developing fetus. In recent papers, Van Calsteren et al. measured transplacental transfer in a baboon model and discovered a significant variation in the percentage of chemotherapy drugs transferred across the placenta [10-12]: Anthracyclines and taxanes had relatively low-percentage transplacental transfer, and were therefore relatively concentrated in the maternal circulation (less than 10% of maternal concentrations in the fetal compartment for anthracyclines, < 2% for taxanes), whereas platinum-based chemotherapy agents were almost completely transferred across the placenta (> 55% of maternal concentrations in the fetal compartment for carboplatin).

Chemotherapy agents associated with high concentration in the fetal compartment tended to be of lower molecular weight and less protein-bound. Similarly, drugs that are substrates of ABC transporters like the permeability glycoprotein also had low fetal concentrations, which may be explained by active transport of these drugs out of the fetal compartment across the placenta by this route.

Pregnancy is associated with a number of physiological changes (see Table 1) that may have an influence on the pharmacokinetics of chemotherapeutic agents. There is an increase in both plasma volume and extracellular fluid volume, which may result in an increased volume of distribution of many drugs, and therefore reducing their peak plasma concentrations. In addition, renal blood flow and, hence, glomerular filtration rate are increased. There is upregulation of enzymes in the cytochrome P450 system in the liver, particularly CYP3A4, which are implicated in the metabolism of a number of chemotherapeutic agents.

Table 1. Physiological changes of pregnancy.

Body system	Change	Effect on pharmacokinetics
Hematological	Increased plasma volume Decreased hematocrit Decreased hemoglobin	Increased volume of distribution
	Increased red cell mass (1400 to 1650 – 1800 ml)
	Increased iron demand
	Increased levels of factor VII Increased levels of factor VIII Increased levels of fibrinogen
Cardiovascular	Increased circulatory volume	Increased volume of distribution
	Increased cardiac output Increased heart rate and Increased stroke volume
	Generalized vasodilation
Renal	Increased renal blood flow Increased GFR	Increased renal clearance
Hepatic	Upregulation of cytochrome P450 system (especially P3A4)	Increased hepatic clearance (of drugs cleared through that pathway)

These changes result in a significant change to the area under the time-concentration curve for many chemotherapy drugs, which has implications for the dose delivery of these agents. Most cytotoxic drugs have steep dose-response curves and narrow therapeutic ratios, which can result in a very sharp divide between efficacious doses and toxic doses. In a recent paper, van Hasselt et al. discovered a significant difference in the plasma concentration-time profiles of several chemotherapy drugs between pregnant and nonpregnant women [13]. In their study, the effects of pregnancy resulted in an approximately 1.32-fold change in the volume of distribution for doxorubicin, a twofold change for epirubicin, a 1.37-fold change for docetaxel and a greater than fourfold change for paclitaxel.

In their conclusion, they stated that a significant dose increase should be applied to compensate for these changes and to obtain the same plasma concentration in pregnant women as in nonpregnant women. Such dose increases may appear surprisingly large, particularly for taxanes, with a calculated dose increase required of approximately 17% for docetaxel and almost 40% for paclitaxel.

The concept of increasing doses of chemotherapy in pregnancy to compensate for the physiological changes of pregnancy is novel, and the implication that pregnant women with cancer are undertreated compared to their nonpregnant counterparts is troubling. However, there is insufficient evidence currently to state that pregnant women with cancer have lower response rates than their nonpregnant counterparts as a result.

Unfortunately, the current research does not tell if these dose adjustments have implications for the efficacy and toxicity of these agents. These are key questions to answer because of the effect that undertreatment would be expected to have on the successful outcome of chemotherapy. A simple randomized controlled trial comparing the adjusted doses with standard doses would seem straightforward to design and implement but, without more data on the effects of these drugs on the long-term health of the fetus, such a study would have significant ethical implications.

However, such research is ongoing, and we can be hopeful that it will be possible for clinicians to give clearer guidance in the future on the effective management of cancer in pregnancy. This is especially important, as the incidence of such cases will increase over the coming years.

Expert opinion

There are two issues with using chemotherapy in pregnancy: First, the effects of chemotherapy exposure in utero on fetal development and the longer-term health of the child. Current studies have found little evidence of significant harm, but recruited small numbers and often relied on parent- or guardian-reported outcomes, which are vulnerable to bias. Those quantitative studies that do exist focus on the effects of in utero exposure to anthracyclines on cardiac function, as measured by echocardiography.

Second, varying transplacental transfer of these drugs and the physiological changes of pregnancy have significant impact on the metabolism and excretion of chemotherapy drugs, with the implication that increased doses would be needed to achieve the same plasma concentrations in pregnancy women and as in nonpregnant women.

However, the implications of these findings for the efficacy of chemotherapy treatment in pregnant women are unclear. Further objective research is needed into the long-term effects on cognitive and physical development of children exposed to chemotherapy in utero. Once we are reassured that the developing fetus is not harmed, we can address the question of whether we undertreat pregnant women by not increasing their chemotherapy doses to compensate for the physiological changes of pregnancy.

By answering these questions, we can feel confident that we are providing the most effective and the safest treatment to pregnant woman with cancer. This will only become more important, as the incidence of cancer in pregnancy rises in the future.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.