The Effect of Veno-Arterial Extracorporeal Oxygenation and Nasogastric Tube Administration on the Pharmacokinetic Profile of Abacavir,Lamivudine and Dolutegravir: A Case Report

Abstract

Background

Pharmacokinetic (PK) changes can affect antiretroviral (ARV) systemic exposure for critically ill patients living with HIV (CI-PLWH). Studies to guide ARV adjustments in this population are limited.

Methods

A PK analysis was conducted in a 44-year-old CI-PLWH who presented for a heart and lung transplant on veno-arterial extracorporeal membrane oxygenation (VA ECMO). Home ARV therapy (ART) of co-formulated abacavir/lamivudine/dolutegravir (ABC/3TC/DTG) was continued. ARV serum concentrations were obtained during and after VA ECMO. Two blood levels were drawn at 1 h, for maximum serum concentration (C_max) and a serum trough (C_t). ARVs were given as a single tablet crushed via nasogastric tube.

Results

Area under the concentration–time curve (AUC_0–t) was calculated using non-compartmental analysis. C_max and AUC_0–t were higher during VA ECMO compared with post-decannulation. The C_max of ABC was >2.5-fold higher than the mean in the reference. C_max and C_t post VA ECMO were within range of referenced literature for all ARVs. C_max and AUC_0–t of DTG post VA ECMO was approximately four- to fivefold lower than referenced literature. HIV virological suppression was maintained throughout the hospitalization.

Conclusions

ART adjustments would not be required for this patient. Additional studies are needed to assess effects of VA ECMO and crushed tube administration of ARVs in CI-PLWH.

Introduction

Pharmacokinetic (PK) changes in critically ill patients living with HIV (CI-PLWH) serve as a challenge when continuing antiretroviral (ARV) therapy (ART) in the hospital [1]. Critical illness, adjustments in medication administration and external support can lead to patient-specific PK changes, altering systemic medication exposure. This includes decreased absorption, increased volume of distribution (V_d), and increased or decreased drug metabolism or clearance depending on medication-specific properties [1–4]. Altered systemic exposure of ARVs may lead to treatment failure, resistance or medication toxicities.

Extracorporeal circuits, including extracorporeal membrane oxygenation (ECMO), can significantly alter PK, primarily through drug sequestration and increased volume of distribution [2,5–7]. To date, only one case report has described ARV PK effects of veno-venous (VV) ECMO [4,8]. In addition, PK studies evaluating administration of crushed ARVs through feeding tubes, which can alter bioavailability, are limited [3]. Drug interactions with tube feed formulations serve as an additional challenge [3,9].

Herein, a PK analysis is described for a CI-PLWH receiving a single tablet regimen (STR) of abacavir/ lamivudine/dolutegravir (ABC/3TC/DTG) administered crushed via nasogastric (NG) tube during veno-arterial (VA) ECMO and post-decannulation.

Patient case

A 44-year-old African American female with HIV was transferred from an outside hospital (OSH) to the University of Maryland Medical Center (UMMC) for heart and lung transplant evaluation. She presented to the OSH with shortness of breath and subjective fevers. Figure 1 provides a hospital course summary. Her past medical history included asthma, pulmonary arterial hypertension (PAH) and gastroparesis. PAH diagnosis was likely secondary to HIV, which were both diagnosed 21 years prior. Her most recent ART was an STR of ABC/3TC/DTG 600/300/50 mg taken by mouth daily, which she self-reported 100% adherence to. Her last HIV RNA was <20 copies/ml and CD4⁺ T-cell count was 764 (25%) cells/μl drawn at the OSH.

Figure 1

Summary of hospital course

She was transferred to UMMC on VA ECMO, vasopressors and intravenous (IV) anti-infectives. Her home ART was continued and administered orally. On hospital day 2, she experienced haemoptysis requiring intubation. Tube feeds were initiated and her medications were switched to be crushed and administered via NG tube. She was extubated on hospital day 5, but reintubated the same day due to recurrent haemoptysis. On hospital day 7 she underwent bilateral orthotopic lung and heart transplant. She received anti-thymocyte globulin for 3 days for induction immunosuppression. She was extubated and decannulated from VA ECMO on hospital day 12.

On hospital day 10, liver enzymes and serum creatinine were elevated, but resolved after 1 day. HIV RNAs drawn on hospital days 2, 6, 11, 20, 27 and 43 were <20 copies/ml. A CD4⁺ T-cell count drawn on hospital day 30, 24 days post-transplantation, was 62 (23%) cells/μl. She was advanced to an oral diet on hospital day 26 and discharged on day 50.

Methods

Ethics

The protocol was approved by the University of Maryland, Baltimore Institutional Review Board. Written informed consent was obtained from the patient prior to sample collection.

Sample Collection and Preparation

Serum concentrations were obtained for ABC, 3TC and DTG on hospital days 12 and 17. Two blood levels were drawn within the same dosing interval for each set; one at 1 h to target maximum serum concentration (C_max) and one before the next dose to target a trough (C_t). During the first set of levels, the patient was cannulated on VA ECMO for 12 days. During the second set, the patient was decannulated from VA ECMO for 5 days (Figure 1). ABC, 3TC and DTG were given as an STR, Triumeq^®, which was crushed and administered via NG tube during both sets of levels. It is not clear whether the tablet was administered with tube feeds or water consistently.

Samples were centrifuged at 4,700 g for 5 min at 4°C, stored at -80°C, then shipped on dry ice to the University of North Carolina Center for AIDS Research Clinical Pharmacology and Analytical Chemistry Core Facility (Chapel Hill, NC, USA) for analysis. Plasma concentrations of ABC, 3TC and DTG were quantified using previously published analytical methods [10]. The calibration curves were linear with a lower limit of quantitation (LLOQ) at 1.00 ng/ml. Assay precision and accuracy were within 15% (20% at LLOQ).

Pharmacokinetic Analysis

Area under the concentration–time curve (AUC) was calculated using non-compartmental analysis. Reported C_max and C_t are reported as direct measured data. Results were compared with published PK studies of non-CI-PLWH receiving each individual ARV as whole tablets [11–13].

Results

Systemic exposures and PK results of ABC, 3TC and DTG are detailed in Table 1 and Figure 2. The C_max and AUC_0–t were higher for the three ARVs during VA ECMO compared with post-decannulation. C_t was similar during ECMO and post-decannulation for all three ARVs. The ABC C_max of 10,200 ng/ml and AUC_0–t of 116,942 ng*h/ml during VA ECMO was higher compared with previously published literature [11]. The 3TC C_max of 2,200 ng/ml during VA ECMO was within range of previous literature. The 3TC C_max of 967 ng/ml post-decannulation was lower that published values [12]. For DTG, the C_max during and after VA ECMO of 1,490 ng/ml and 607 ng/ml, respectively, was lower compared with the literature [13]. The DTG AUC_0–t was lower during and after VA ECMO of 21,523 and 11,704 ng*h/ml, respectively, compared with the literature.

Figure 2

Concentration versus time post dose

Conclusions

This case report characterizes PK of ABC, 3TC and DTG administered as an STR, crushed via NG tube, in a CI-PLWH during and after VA ECMO. The C_max and AUC_0–t were higher for all three ARVs during ECMO compared with post-decannulation. ABC C_max was >2.5-fold higher during ECMO than the C_max seen in literature (Table 1). DTG C_max and AUC_0–t post-ECMO were approximately four- to fivefold lower than the mean observed in literature [11]. Because C_t remained above the protein-adjusted 90% inhibitory concentration (IC₉₀) for wild-type HIV of 64 ng/ml, this decrease is likely clinically insignificant [13]. Specific to DTG, trough concentrations in the SPRING-1 trial suggest a clinical target trough of 300 ng/ml, 4x higher than the protein-adjusted IC₉₀ [14]. DTG trough concentrations in this report of 409 ng/ml and 415 ng/ml during and post VA ECMO, respectively, exceeded this higher threshold. No events during the hospital course were attributed to ARV toxicities and the patient remained virally suppressed.

Table 1

Pharmacokinetic parameters of ABC, 3TC and DTG during and after VA ECMO compared with reference studies

	During VA ECMO			Post VA ECMO			Reference
Agent	AUC_0–t, ng*h/ml	C_max ng/ml	C_t, ng/ml	AUC_0–t, ng*h/ml	C_max, ng/ml	C_t, ng/ml	Mean AUC_0–t, ng*h/ml	Mean C_max, ng/ml (95% CI)	Mean C_t, ng/ml (95% CI)
ABC	116,942	10,200	14	27,156	2,300	22	8,520	3,850 (1,001, 6,699)	9 (0, 27)
3TC	29,041	2,200	353	15,483	967	376	16,644	3,461 (1,799, 5,122)	146 (0, 320)
DTG	21,523	1,490	409	11,704	607	415	43,400	3,340 (2,271, 4,409)	830 (398, 1,262)

ABC, abacavir; AUC, area under the concentration–time curve; C_max, maximum concentration; Ct, concentration at the end of the dosing interval; DTG, dolutegravir; VA ECMO, veno-arterial extracorporeal oxygenation; 3TC, lamivudine.

A case report describing effects of ECMO on ARV PK assessed serum levels of ritonavir (RTV), darunavir (DRV), 3TC and tenofovir (TFV) in a CI-PLWH undergoing VV ECMO. Apart from 3TC, the other ARVs were given at empiric double doses. RTV and TFV serum levels were lower than expected, whereas DRV levels were higher, although the PK fell within the expected range of population PK models. 3TC was observed to exhibit a PK profile out of expected range compared with a population PK model [8].

Studies evaluating effects of crushing and administering ARVs through enteral feeding tubes are limited. Although ABC and 3TC have commercially available solutions, DTG is currently only available as a tablet, which must be crushed for tube administration. A prospective study evaluating PK after a single dose of ABC/3TC/DTG taken crushed by mouth in 22 healthy volunteers found variability among ARV systemic concentrations. Compared with population PK, ABC was bioequivalent when administered with water, 3TC was bioequivalent when administered with water and the enteral feed, and DTG was not bioequivalent when mixed with either. Specifically, the DTG AUC_0–t and C_max was 26% and 30% higher compared with references [15]. Few case reports assess crushed DTG in PLWH [16–19]. One case report described a CI-PLWH where DTG was increased to 50 mg twice daily given crushed via gastrostomy tube. The DTG C_t of 820 ng/ml following the higher 50 mg twice daily dosing was similar to the reference of 830 ng/ml with 50 mg daily dosing. Another case report in a CI-PLWH found that DTG exposure was similar when administered oral versus jejunostomy tube, but the AUC exposure was 76% and 75% lower compared with the literature, respectively [17]. Similar to the current report, all previous reports describe maintenance of viral suppression with altered DTG administration [16–19].

In the current report, it is unclear why increased C_max and AUC_0–t were observed for ABC, 3TC and DTG during ECMO compared with post-decannulation. This observation is not thought to be due to ECMO alone. ECMO mainly increases medication V_d through drug sequestration in the circuit. Lipophilic and highly protein bound medications are thought to be the most affected [7]. DTG exhibits the highest lipophilicity and protein binding compared with 3TC, which exhibits the lowest. Critical illness and subsequent hypoperfusion of liver and kidney is thought to most directly affect medication metabolism and clearance [7]. The patient had a slight increase in liver enzymes and serum creatinine around the time of blood collection. However, this is thought to be non-contributory given the change persisted for <2 days. It is also possible the tube formulation switch and increase in total percentage of tube feed received post-ECMO could have altered ARV absorption.

Limitations of this study include the critical status of this patient. There are many factors that could affect the PK profile of ARVs outside of NG tube administration and VA ECMO. Additionally, only two concentrations were obtained, limiting the ability to draw conclusions over the entirety of the dosing interval. Also, the C_max was drawn at 1 h, which was selected based on C_max of the three different ARVs, although the exact C_max of each individual ARV differs. Lastly, there was a delay in obtaining plasma concentrations, which were completed and obtained once the patient was taking medications orally; therefore, results were not used to adjust the patient's ART.

Future studies are required to characterize ARV PK during ECMO and when administered crushed for enteral tube feed for CI-PLWH. Based on our findings, alterations in PK with crushed ABC/3TC/DTG in a patient on VA ECMO did not result in a change in HIV viral suppression.

Footnotes

Acknowledgements

We would like to thank Amanda P Schauer at the Center for AIDS Research Clinical Pharmacology & Analytical Core, Chapel Hill, NC, USA, for her analysis of the anti-retroviral plasma samples. We would also like to thank Mackenzie Cottrell at the Center for AIDS Research Clinical Pharmacology & Analytical Core, Chapel Hill, NC, USA, for her compilation of the TDM report. ASD is supported by the National Institute of General Medical Sciences of the NIH under Award Number T32GM086330. The content is solely the responsibility of the authors and does not necessarily represent the official views of National Institutes of Health.

The authors declare no competing interests.

References

Lanoix

J-P

, Andrejak

, Schmit

J-L

. Antiretroviral therapy in intensive care. Med Mal Infect 2011; 41: 353–358.

Hahn

, Choi

J.H.

, Chang

M.J.

Pharmacokinetic changes of antibiotic, antiviral, antituberculosis and antifungal agents during extracorporeal membrane oxygenation in critically ill adult patients. J Clin Pharm Ther 2017; 42: 661–671.

Huesgen

, DeSear

K.E.

, Egelund

E.F.

, Smith

, Max

, Janelle

A HAART-breaking review of alternative antiretroviral administration: practical considerations with crushing and enteral tube scenarios. Pharmacotherapy 2016; 36: 1145–1165.

Giguère

, la Porte

, Zhang

, Cameron

Pharmacokinetics of darunavir, etravirine and raltegravir in an HIV-infected patient on haemodialysis. AIDS 2009; 23: 740–742.

Sherwin

, Heath

, Watt

Pharmacokinetics and dosing of anti-infective drugs in patients on extracorporeal membrane oxygenation: a review of the current literature. Clin Ther 2016; 38: 1976–1994.

M.A.

, Sieg

A.C.

Evaluation of altered drug pharmacokinetics in critically ill adults receiving extracorporeal membrane oxygenation. Pharmacotherapy 2017; 37: 221–235.

Cheng

, Abdul-Aziz

M-H

, Roberts

J.A.

, Shekar

Optimising drug dosing in patients receiving extracorporeal membrane oxygenation. J Thorac Dis 2018; 10 Suppl 2: S629–S641.

Ghazi Suliman

M.A.

, Ogungbenro

, Kosmidis

The effect of veno-venous ECMO on the pharmacokinetics of ritonavir, darunavir, tenofovir and lamivudine. J Crit Care 2017; 40: 113–118.

Nyberg

C.R.

, Patterson

B.Y.

, Williams

M.M.

When patients cannot take pills: antiretroviral drug formulations for managing adult HIV infection. Top Antivir Med 2011; 19: 126–131.

10.

Leibrand

C.R.

, Paris

J.J.

, Jones

A.M.

HIV-1 Tat and opioids act independently to limit antiretroviral brain concentrations and reduce blood-brain barrier integrity. J Neurovirol 2019; 25: 560–577.

11.

Moyle

, Boffito

, Fletcher

Steady-state pharmacokinetics of abacavir in plasma and intracellular carbovir triphosphate following administration of abacavir at 600 milligrams once daily and 300 milligrams twice daily in human immunodeficiency virus-infected subjects. Antimicrob Agents Chemother 2009; 53: 1532–1538.

12.

Bruno

, Regazzi

M.B.

, Ciappina

Comparison of the plasma pharmacokinetics of lamivudine during twice and once daily administration in patients with HIV. Clin Pharmacokinet 2001; 40: 695–700.

13.

Min

, Sloan

, DeJesus

Antiviral activity, safety, and pharmacokinetics/pharmacodynamics of dolutegravir as 10-day monotherapy in HIV-1-infected adults. AIDS 2011; 25: 1737–1745.

14.

van Lunzen

, Maggiolo

, Arribas

J.R.

Once daily dolutegravir (S/GSK1349572) in combination therapy in antiretroviral-naive adults with HIV: planned interim 48 week results from SPRING-1, a dose-ranging, randomised, Phase 2b trial. Lancet Infect Dis 2012; 12: 111–118.

15.

Roskam-Kwint

, Bollen

, Colbers

, Duisenberg-van Essenberg

, Harbers

, Burger

Crushing of dolutegravir fixed-dose combination tablets increases dolutegravir exposure. J Antimicrob Chemother 2018; 73: 2430–2434.

16.

Turley

S.L.

, Fulco

P.P.

Enteral administration of twice-daily dolutegravir and rilpivirine as a part of a triple-therapy regimen in a critically ill patient with HIV. J Int Assoc Provid AIDS Care 2017; 16: 117–119.

17.

Brooks

K.M.

, Garrett

K.L.

, Kuriakose

S.S.

Decreased absorption of dolutegravir and tenofovir disoproxil fumarate, but not emtricitabine, in an HIV-infected patient following oral and jejunostomy-tube administration. Pharmacotherapy 2017; 37: e82–e89.

18.

Chrdle

, Jerhotová

, Vacík

, Linka

, Chmelík

Crushed dolutegravir/abacavir/lamivudine given via nasogastric tube in gastric outlet obstruction caused by cancer resulted in rapid viral load suppression. Int J STD AIDS 2019; 30: 94–98.

19.

Buscemi

Virological suppression after use of crushed tenofovir-emtricitabine and dolutegravir tablets in a patient with HIV infection. Am J Health Syst Pharm 2016; 73: 1125–1126.