Self‐poisoning with 60 tablets of Apixaban, a pharmacokinetics case report

Abstract

A 67‐year‐old man was admitted to the emergency department about 5 h after deliberate self‐poisoning with 300 mg of Apixaban. The clinical examination did not show any organ dysfunctions or haemorrhagic signs, and the patient's life was not in danger. The first analysis, upon admission, showed a concentration of 2655 μg l⁻¹ of Apixaban. The Cmax was observed 17 h after the intake (3654 μg l⁻¹), about four times the classical Tmax value (median [range]: 4 h [2–4]). The Apixaban was then eliminated following a first order elimination with a calculated half‐life of 10.8 h. The anti‐Xa activity seems to be linearly related to concentration up to 4000 μg l⁻¹. This report suggests that the use of activated charcoal should be effective up to 17 h after a massive intake.

Context

Apixaban is an oral anticoagulant which acts by selective and reversible inhibition of factor Xa 1, 2. Oral anticoagulants are commonly used for the prevention and treatment of thromboembolic diseases 2. Unlike vitamin K antagonists, it does not require any biological monitoring 2. In case of overdosing, there is currently not specific antidote and treatment is only symptomatic.

Case

A 67‐year‐old man with a medical history of depression was admitted to the emergency department after deliberate self‐poisoning. His medical history included a heart attack and high blood pressure treated by beta‐blockers (bisoprolol), anticoagulant (Apixaban), antianginal drugs (Nitroglycerin and Nicorandil), diuretic (Furosemide) and statins, diabetes treated by insulin and a severe depression treated by antidepressants (Vortioxetine) and anxiolytic benzodiazepine (Oxazepam). Upon admission, the patient explained that 5 h earlier, he had taken 60 tablets of Apixaban, 16 g of Acetaminophen, approximatively 10 tablets of Oxazepam and a few other drugs (not specified). The clinical examination did not show any organ dysfunctions or haemorrhagic signs, and the patient's life was not in danger. The first toxicological tests, carried out on admission, revealed an undetectable alcohol blood concentration and an acetaminophen plasma concentration at 86.3 mg l⁻¹ (therapeutic trough concentrations between 5 and 25 mg l⁻¹). N‐acetylcysteine was initiated to prevent hepatic injury while no other medication was initiated. Activated charcoal was not used because more than 6 h had passed since the drug intake. Indeed, it has been shown that activated charcoal administered between 2 to 6 h after intake reduces the area under the curve and half‐life at therapeutic doses 2, 3. As Apixaban exposure is closely correlated to the anti‐Xa activity, the drug measurement of Apixaban is not performed 24 h/24 h in our laboratory. Three measurements were performed during hospitalization, at 16.8, 39.7 and 70.8 h after the intake leading to plasma concentrations, estimated using the anti‐Xa activity, of 2703, 570 and 109 μg l⁻¹, respectively.

The patient remained under medical supervision for 2 days and was then transferred to the psychiatric. Ironically, Apixaban was reintroduced 6 days later as the patient had a suspected pulmonary embolism (PE) based on clinical signs (chest pains and breathlessness). However, the diagnosis was excluded by the D‐dimer results (below the cut‐off level of 680 μg l⁻¹) which were 448 μg l⁻¹ when PE was suspected and 424 μg l⁻¹ 7 days later.

Analytical Methods

After a deproteinization step using QuECHERS salts and acetonitrile, chromatographic separation was performed using a 2.7‐μm C18 column (5.0 × 2.1 mm i.d., AMT Halo, Interchim, France). Detection was performed using an 8050 liquid chromatography – tandem mass spectrometry system equipped with an electrospray ionization source used in a positive ionization mode (Shimadzu, France) and a detection in MRM mode following one transition for quantitation and one transition for confirmation. The limit of quantification of Apixaban was 2.5 μg l⁻¹, and the method was linear up to 500 μg l⁻¹. 13C2H7‐apixaban was used as internal standard.

Investigations

A posteriori drug measurement of Apixaban using LC/MS/MS showed a concentration of 2655 μg l⁻¹ for the first sample, upon admission. Four more blood samples were collected while the patient was hospitalized in the intensive care unit, at 16.8, 39.7, 65 and 113 h after the drug intake and LC/MS/MS drug measurement exhibited Apixaban concentrations of 3654, 980, 130 and 6 μg l⁻¹, respectively – therapeutic concentrations usually observed for an intake of 5 mg twice a day rank between 49.6 μg l⁻¹ (Cmin) and 128.5 μg l⁻¹ (Cmax) 4. The elimination was almost complete 113 h after the drug intake. The measured Tmax was about 17 h (Cmax = 3654 μg l⁻¹). A first‐order elimination was observed, and the calculated apparent half‐life was 10.8 h.

As anti‐Xa activity and LC/MS/MS concentrations of Apixaban were simultaneously available for only two samples, no correlation was calculated. However, as shown in Figure 1, there was an excellent overlap between these two markers.

Figure 1.

Concentration versus time profile of Apixaban, anti‐Xa activity and prothrombin time after massive ingestion of 300 mg pills of Apixaban

Discussion

In this clinical case of Apixaban intoxication, we found concentrations approximately 28‐fold higher than therapeutic concentrations, a largely delayed Tmax but a normal elimination half‐life. Another important finding is that anti‐Xa activity seems to be linearly related to concentrations up to 4000 μg l⁻¹. This is the fourth published case of self‐poisoning with Apixaban 5, 6, 7, with the highest concentrations reported so far. The apparent half‐life is close to the usual value at therapeutic doses (mean/SD: 11.7 h/3.3) 4. Apixaban absorption is usually described as linear up to 10 mg and non‐linear beyond, with clearly decreased dissolution, absorption and bioavailability at doses higher than 25 mg 2. As previously described, a delayed absorption was observed with a Tmax at 17 h, about four times the usual Tmax value (median [range]: 4 h [2–4]) 4. This can be explained by the high number of tablets ingested (~100) which could have formed an agglomeration of pills and limited the dissolution of the tablets and prolonged absorption of the drug. Another hypothesis would be a saturation of the intestinal cytochromes and transporters or metabolism by the high amount of Apixaban and other medication. Indeed, Apixaban is mainly metabolized by cytochrome P450 family 3 subfamily A member 4 (CYP3A4/5) and is a substrate of P‐glycoprotein (ABCB1) and Breast Cancer Resistance Protein (ABCG2) 8. ABCB1 and ABCG2 are both intestinal efflux transporters that may be involved in the enteroenteric recirculation of Apixaban observed in animal studies 9. The saturation of these transporters might explain the increase in the Apixaban concentration due to a diminution of its efflux.

Some authorities and studies suggest using activated charcoal within the first 2 h following massive ingestion 10, 11. Indeed, the apparent half‐life of Apixaban alone (dose of 20 mg) or with activated charcoal administered 2 or 6 h after ingestion is reduced from 13.4 to 5.3 h or 4.9 h, respectively. Accordingly, Apixaban AUC decreases from 4.185 to 2.034 ng h ml⁻¹ or 2.976 ng h ml⁻¹ for Apixaban alone (dose of 20 mg) or administered with activated charcoal 2 or 6 h after ingestion, respectively 3. In the present case, due to the lack of epuration treatment, the Apixaban concentration remained above the upper therapeutic limit for more than 65 h, drastically increasing the risk of bleeding. Taking into account the observed modification of its pharmacokinetic and with the knowledge that activated charcoal is effective on Apixaban, its use on admission might have reduced Apixaban exposure 12. The other medications used to treat overdosing such as non‐specific reversal agents and specific reversible agents (not yet available), and their use in the treatment of Apixaban bleeding complications are not discussed in the present case but are well described by Gonsalves et al. 10.

Conclusion

Due to delayed absorption of the drug, this case report suggests that activated charcoal may be effective even when used beyond the 6th hour after a massive ingestion of Apixaban, in order to reduce overexposure. Except in cases of urgent surgery or major bleeding when a specific antagonist has to be used, activated charcoal seems to be an acceptable alternative for the treatment of overdosing. In any case, special attention should be paid to plasma drug levels or anti‐Xa activity to know when to reintroduce the drug.

Nomenclature of targets and ligands

Key protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY 13, and are permanently archived in the Concise Guide to PHARMACOLOGY 2017/18 8, 14.

Competing Interests

There are no competing interests to declare.

We are grateful to K. Poole for manuscript editing.

Franck, B. , Dulaurent, S. , El Balkhi, S. , Monchaud, C. , Picard, N. , Couderc, S. , Marquet, P. , Saint‐Marcoux, F. , and Woillard, J.‐B. (2019) Self‐poisoning with 60 tablets of Apixaban, a pharmacokinetics case report. Br J Clin Pharmacol, 85: 270–272. 10.1111/bcp.13790.