Novel drugs approved in 2016

Pimavanserin (Nuplazid) is an atypical antipsychotic indicated for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis. Reproduction studies in animals suggest low risk. The molecular weight of the free base (about 428) and the long mean plasma half-lives of the parent drug and active metabolite (57 and 200 hours) suggest that the drug will cross the placenta. However, the high plasma protein binding (about 95%) may limit the exposure. Nevertheless, avoiding the period of organogenesis appears to be best.

Dermatologic agents

Crisaborole (Eucrisa) is indicated for topical treatment of mild to moderate atopic dermatitis. In 33 pediatric subjects (aged 2-17 years) who applied the ointment twice daily for 8 days, low amounts were absorbed systemically with plasma concentrations in the nanogram/milliliter range. Plasma protein binding was 97%. With oral formulations of the drug, animal reproduction studies suggest low risk. Taken in sum, the human pregnancy risk appears to be low.

Ixekizumab (Taltz) is a humanized interleukin-17A antagonist, administered subcutaneously, that is indicated for the treatment of adults with moderate to severe plaque psoriasis. The drug did not cause developmental toxicity in monkeys. The molecular weight for the drug’s protein backbone is 146,158, and the mean elimination half-life was 13 days. The human embryo-fetal risk in the first half of pregnancy appears to be low.

Diagnostic agents

Fluciclovine F 18 (Axumin) is a radioactive diagnostic agent indicated for positron emission tomography imaging in men with suspected prostate cancer. Since the agent is only used in men, there are no human or animal pregnancy data.

Gallium GA 68 dotatate injection, a diagnostic imaging agent to detect rare neuroendocrine tumors, is not yet on the market.

Endocrine/metabolic agents

Lixisenatide (Adlyxin) is a glucagon-like–peptide-1 receptor agonist that is administered subcutaneously. It is indicated as an adjunct to diet and exercise to improve glycemic control in type 2 diabetes. The drug was teratogenic in two animal species. The molecular weight is about 4,859, and the mean terminal half-life was about 3 hours. Since tight control of glucose levels in type 2 diabetes is required during pregnancy, insulin is the treatment of choice. Consequently, lixisenatide should not be used during pregnancy.

Gastrointestinal agents

Obeticholic acid (Ocaliva) is a farnesoid X receptor agonist that is given orally for the treatment of primary biliary cholangitis, in combination with ursodiol, or ursodeoxycholic acid. I have classified ursodiol as compatible in pregnancy in the 10th edition of “Drugs in Pregnancy and Lactation” (2011: Wolters Kluwer Health). The animal reproduction data for both drugs suggest low risk. Based on the molecular weight of obeticholic (about 421), the drug will probably cross to the embryo/fetus, but the high plasma protein binding (greater than 99%) may limit exposure. The elimination half-life is apparently unknown.

Hematologic agents

Defibrotide sodium (Defitelio), given as an intravenous infusion, is an oligonucleotide mixture. It is indicated for the treatment of hepatic veno-occlusive disease, also known as sinusoidal obstruction syndrome, with renal or pulmonary dysfunction following hematopoietic stem-cell transplantation. Animal reproduction studies in two species suggest risk. The mean molecular weight is 13,000-20,000. Plasma protein binding is an average 93%, and the elimination half-life is less than 2 hours. It is doubtful if the drug crosses the placenta, especially in the first half of pregnancy. If possible, avoid the drug in the second half of pregnancy.

Immunologics

Two indications have been approved for daclizumab. The first was in 2005 for the prophylaxis of acute organ rejection of renal transplants (Zenapax), and the second was in 2016 for the treatment of relapsing forms of multiple sclerosis (Zinbryta). Reproduction studies in monkeys with Zinbryta can be classified as low risk. The molecular weight (about 144,000) suggests that the drug will not cross the placenta, at least in the first half of pregnancy. However, depending on when the drug is given, the long elimination half-life of 21 days might allow the drug to cross in late pregnancy. Regardless, if the perceived maternal benefit exceeds the potential embryo-fetal risk, the drug should not be withheld because of pregnancy.

Muscular disorder agents

Eteplirsen (Exondys 51) is an antisense oligonucleotide that is given intravenously. It is indicated for the treatment of Duchenne muscular dystrophy in patients who have a confirmed mutation of the related gene, which is amenable to exon 51 skipping. There are no animal reproduction data. The molecular weight is about 10,306. This suggests that the drug will not cross the placenta, at least in the first half of pregnancy. The elimination half-life is 3-4 hours, and the plasma concentration 24 hours after a dose was 0.07% of the peak plasma concentration. The drug is given once weekly, and waiting for 24 hours or slightly longer after a dose should reduce the exposure, if any, of the embryo-fetus during the first half of pregnancy.