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Correspondence

Boosted darunavir, emtricitabine and tenofovir pharmacokinetics in the early and late postgastric bypass surgery periods

Baettig, Veronikaa,b; Courlet, Perrinec; Delko, Tarikb,d; Battegay, Manuela,b; Marzolini, Catiaa,b

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doi: 10.1097/QAD.0000000000001913
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The impact of bariatric surgery on antiretroviral pharmacokinetics is poorly documented. Common surgical interventions for morbid obesity include diversionary procedures such as Roux-en-Y gastric bypass (RYGB) and restrictive procedures such as sleeve gastrectomy. Both procedures consist of creating a small portion of the stomach resulting in decreased gastric volume and increased gastric pH, which may impair the absorption of drugs whose solubility relies on low gastric pH (e.g. rilpivirine, atazanavir). In the case of RYGB, the gastric pouch is attached to the small intestine, thereby partially bypassing the duodenum and jejunum. Consequently, RYGB may further impact drug absorption due to a reduced exposure to the intestinal mucosa. Maintenance of sufficient antiretroviral drug exposure is critical given the risk of viral relapse. Thus, the characterization of antiretroviral drugs pharmacokinetics after bariatric surgery is of clinical interest to provide dosage recommendations both in the early and late postoperative periods.

We report a 43-year-old HIV-infected woman undergoing RYGB (BMI: 47.5 kg/m2). At the time of surgery, the patient was virologically suppressed with a CD4+ cell count of 1040 cells/μl under once-daily treatment with darunavir/ritonavir (800/100 mg), emtricitabine (200 mg) and tenofovir disoproxil (245 mg). Routine therapeutic drug monitoring (TDM) performed 3 months before surgery showed plasma levels of darunavir/ritonavir, emtricitabine and tenofovir more than 75th percentile (5314/450; 428 and 121 ng/ml, 14 h after drug intake). We anticipated that RYGB might alter antiretroviral drug exposure; therefore, darunavir/ritonavir was increased immediately postsurgery to 600/100 mg twice daily, whereas emtricitabine and tenofovir dosages were unchanged. This dosing recommendation followed published data reporting adequate single-point measurement of these antiretrovirals, although 1-year post-RYGB [1]. Thus, the reported levels might not reflect the early postoperative period as the intestine could have adapted to compensate for the altered physiology. Due to the paucity of data, we decided to document the pharmacokinetic profiles of darunavir/ritonavir, emtricitabine and tenofovir in the early and late post-RYGB periods. During the morning of the pharmacokinetic investigations, the patient took darunavir/ritonavir with a small breakfast then blood samples were drawn at defined time points over 12 h. Given the once-daily administration of emtricitabine and tenofovir, their pharmacokinetics was measured from 12 to 24-h post-intake. Drug levels were quantified using validated liquid chromatography coupled to tandem mass spectrometry methods [2,3]. The drug profiles drawn from compartmental analyses and the pharmacokinetic parameters calculated using noncompartmental analysis are presented in Fig. 1.

Fig. 1
Fig. 1:
Drug plasma profiles measured in the patient with the corresponding reference profiles issued from published population pharmacokinetic analyses.Darunavir [600 mg twice a day (BID)] (a), Ritonavir (100 mg BID) (b), emtricitabine [200 mg once a day (QD)] (c) and tenofovir (245 mg QD) (d) pharmacokinetic profiles 3 days (filled squares) and 10 weeks (open squares) post gastric bypass surgery. Grey dashed lines represent the 2.5 or 10, 97.5 or 90th percentile and grey continuous lines 50th percentile concentration curves derived from published population-based pharmacokinetic models of darunavir/ritonavir [4], emtricitabine [7] and tenofovir [8]. The area under the curve (AUC)0–12h, C max, C min, half-life of darunavir 3 days and 10 weeks after surgery were 30 996 and 60 031 ng h/ml, 5574 and 6967 ng/ml, 1166 and 3350 ng/ml, 7.4 and 11.6 h, respectively. For ritonavir, the AUC0–12h, C max, C min, half-live were 1717 and 10 620 ng h/ml, 277 and 1819 ng/ml, 40 and 384 ng/ml, 3.4 and 5.2 h, respectively.

Compared with reference pharmacokinetic profiles and parameters [4,5], darunavir area under the curve (AUC)0–12h, Cmax and Cmin 3 days postsurgery were decreased by 50, 14 and 67%, whereas darunavir exposure 10 weeks postsurgery was comparable with reference (Fig. 1a). Ritonavir AUC0–12h, Cmax and Cmin 3 days postsurgery were decreased by 67, 67 and 75% compared with reference [4,6], whereas ritonavir pharmacokinetic parameters were increased by 104, 119 and 135% 10 weeks postsurgery (Fig. 1b). Compared with references [7,8], emtricitabine exposure was at percentile 10th and close to 50th 3 days and 10 weeks postsurgery (Fig. 1c), whereas tenofovir exposure was at percentile 50th and above 75th, respectively (Fig. 1d). Given the normal drug exposures on the second pharmacokinetic investigation, the patient was changed back to a once-daily darunavir/ritonavir (800/100 mg) schedule. One-year postsurgery TDM showed good levels of darunavir/ritonavir, emtricitabine and tenofovir (changed to tenofovir alafenamide) (3140/298; 147 and 11 ng/ml, 14 h after drug intake).

This report describes for the first time the full pharmacokinetic profiles of darunavir/ritonavir in the early and late postsurgery periods. Darunavir exposure underwent a marked transient reduction as explained by the impaired absorption in the early postsurgery period of darunavir and notably of ritonavir, thus altering in turn its boosting effect on darunavir pharmacokinetics. Despite this decrease, darunavir levels remained well above the protein-adjusted concentration inhibiting viral replication by 90% for the wild-type virus (55 ng/ml) [4] and the patient remained virologically suppressed throughout. The administration of once-daily darunavir/ritonavir could likely have been possible in this patient given the good presurgery drug exposure. The extrapolated Cmin, 24h is ≈410 ng/ml, thus still within the observed darunavir Cmin range for once-daily administration [median (95% prediction interval): 981 (110–4449) ng/ml] [4]. However, the observed 67% decrease in darunavir Cmin early postsurgery could be problematic in patients with resistant viruses, particularly if the presurgery level is below percentile 50th. The transient decrease in tenofovir exposure with maintenance of viral suppression is in line with published data [9]. This case highlights the utility of TDM to guide dosage recommendations in patients undergoing bariatric surgery [10].

Acknowledgements

The authors thank Ms Susana Alves Saldanha for her excellent analytical support, as well as the patient.

Conflicts of interest

There are no conflicts of interest.

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