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Factors influencing pharmacokinetic changes following restrictive and metabolic bariatric surgery

Pharmacokinetic (PK) changes following both restrictive and metabolic bariatric surgery are drug-specific and highly variable according to the type of surgery, duration of the follow-up and inter-individual post-operative characteristics, according to a meta-analysis and systematic review by an international team of researchers.

“To our knowledge, this is the first meta-analysis and systematic review examining medication and supplement absorption following bariatric and metabolic surgery", the authors noted. "This study offers a new insight into PK changes in a large spectrum of drugs and supplements following bariatric surgery, and its high-quality, standardised methodology is rigorously conducted."


In order to evaluate the impact of bariatric surgery on the PK parameters of orally administered medications and supplements, the researchers performed a systematic search of bibliographic databases were conducted to identify studies. Pooled effect estimates from different surgical procedures were calculated using a random-effects model.


They identified 58 studies (1985 participants) including 40 medications and six supplements. After analysis, meta-analysis included the following medications and supplements: atorvastatin, paracetamol, omeprazole, midazolam, vitamin D, calcium, zinc and iron supplements. The aim was to comprehensively assess the PK outcomes of these specific drugs and supplements following the most frequently performed bariatric or metabolic procedures (SG, GB, RYGB, DBP, OAGB and SADI).


The mean age of participants included in the meta-analysis was 43.0 years old with 1,111 (82.7%) of them being female. A total of 146 (10.2%) participants underwent a restrictive surgical procedure (SG) and 1,299 (91.0%) underwent metabolic surgeries (1,279 participants had an RYGB and 20 underwent a DBP). The type of surgery was not specified (either SG or RYGB) for 24 participants (1.6%). Ten studies collected surgical details, such as limb length. For RYGB, the mean alimentary limb length was 88.4cm, and the mean bypass length was 131.2cm. In cases of DBP, the mean bypass length was 120 cm and the common length was 87.5 cm.


Outcomes

A total of three studies (44 participants) were included for the analysis of atorvastatin pre-and post-operative PK parameters (Cmax and Tmax). Overall, 24 participants (54.5%) underwent RYGB, and 20 (45.4%) had BPD. Following malabsorptive procedures, atorvastatin Cmax tended to decrease and Tmax tended to increase, but changes in those parameters were not significant.

PK Cmax of oral midazolam was assessed in three studies including 51 participants, of which all underwent RYGB. Following a mean post-operative period of 88.9 weeks, participants lost a mean of −0.16 ± 0.05 kg/m2/week. Oral midazolam Cmax did not significantly change following bariatric or metabolic surgery.


They identified three studies that reported on omeprazole CL/F,37-39 and four studies which reported on Omeprazole Cmax and Tmax after surgery (97 participants included, 41 (42.3%) underwent SG and 56 (57.7%) had RYGB). After a mean of 18.9 weeks and a mean weight loss of −0.57±0.26kg/m2/week, none of the omeprazole PK significantly changed.


Overall, three studies were included for the analysis of paracetamol pre- and post-bariatric or metabolic surgery parameters and reported on CL/F, Vd/F, Cmax, Tmax, and T1/2. A total of 40 participants were included, of which 7 (17.5%) underwent SG, 9 (22.5%) had RYGB and 24 (60%) had either SG or RYGB. Participants lost a mean of −0.34kg/m2/week and the mean post-operative follow-up was 29.7 weeks. Following bariatric/metabolic surgery, paracetamol Vd/F and Tmax did not change; however, Cmax significantly increased [mean difference of +6.90, (95% CI -3.09 to 16.89) μg/ml]. Comparably, T1/2 was increased and CL/F was reduced [mean differences of +0.49 (95% CI 0.27 to 0.70) h and −18.28 (95% CI -27.98 to −8.58) L/h, respectively].


Differences in vitamin D levels were described in nine studies (1,102 participants in total, of which 116 (10.5%) underwent SG, 897 (81.4%) had RYGB, and 89 (8.1%) had either SG or RYGB) reporting a mean follow-up of 67.7 weeks and a mean weight loss of −0.36 ± 0.06 kg/m2/week. The results demonstrated a positive increase in vitamin D levels following bariatric or metabolic surgery and oral supplements (+5.40 [95%CI 2.12 to 6.68] ng/ml). A sub-group analysis was performed to assess pre- and post-op differences in vitamin D level, as compared between types of bariatric surgery (restrictive [SG] vs metabolic [RYGB]). The sub-group analysis from six studies reporting on changes in vitamin D levels before and after RYGB with oral supplementation did show an increase in vitamin D levels post-op. The majority of the difference reported from the initial analysis was contributed by the SG group; the results from five studies on SG showed a significant increase in vitamin D levels with various forms of oral supplementation (+10.33 [95%CI 9.70 to 10.95] ng/ml).


Pre- and post-operative serum calcium levels were described in four studies (572 participants, 65 (11.4%) participants had SG, 418 (73.0%) had RYGB, and 89 (15.6%) one or the other procedure). At 36 weeks post-operatively, with a mean weight loss of −0.35 ± 0.07 kg/m2/week and oral calcium supplementation, levels of serum calcium levels did not statistically significantly change compared to the baseline.


Two studies reporting on changes in zinc levels before and after surgery with supplementation (75 participants in total, 19 (25.3%) participants with SG and 56 (74.7%) with RYGB, mean follow-up of 24 weeks and mean weight loss of −0.48 ± 0.08 kg/m2/week), the analysis did not show a statistically significant difference between baseline and post-operative levels.


Two studies (three arms) were included for the analysis of pre- and post-operative ferritin levels following bariatric/metabolic surgery. A total of 75 participants (30 (40.0%) participants with SG and 45 participants (60.0%) with RYGB) were included, with a mean follow-up of 24 weeks post-operatively and a mean weight loss of −0.43 ± 0.03 kg/m2/week. Following bariatric or metabolic surgery and whilst on iron supplements, ferritin levels did not change significantly.


Studies included in the systematic review are grouped by type of bariatric surgery (restrictive or metabolic), two studies did not distinguish between SG or RYGB, thus results were reported in both tables (caffeine and midazolam).


A total of eight studies were assessed on 8 different medications and including 110 participants who underwent SG, revealed absorption (estimated using AUC and/or Cmax) remained unchanged following bariatric surgery for most medications, except for 1) carbamazepine, whereby levels decreased following SG,59 2) tacrolimus, where C0 increased from 9 to 12 months post-operatively (n=12, patients in chronic renal failure), 3) rivaroxaban, where Cmax increased when assessed shortly after SG (n=6, measured between one- and three-days post-op), but only in one study.


Thirty studies reporting on PK outcomes of oral bioavailability following metabolic surgery (RYGB or BPD) with a total of 33 medications and 430 participants. A majority of studies did not report significant changes in oral absorption following metabolic surgery. Evidence for diminished oral bioavailability was found for rosuvastatin (C0, within the first year post-op) and sertraline (AUC0–10.5 and Cmax, after more than one year post-op). Comparisons of pre- and post-operative PK parameters showed increased oral bioavailability for simvastatin (C0) (although parent and metabolite concentrations were normalised for doses and body weight), warfarin (INR and warfarin dose/INR ratio), metformin [oral bioavailability, Area under the curve (AUC0–∞)] and morphine (Tmax, Cmax, AUC0–12, and AUC 0-∞) when measured within one year following surgery.

In terms of trace elements and supplements, the results of one study reporting on systemic vitamin and essential trace element levels were included in the systematic review for the SG group.


Copper and B12 systemic levels remained unchanged at six months following surgery in patients taking a daily multivitamin containing 2mg of copper and 100mcg of B12. Examining supplement absorption following metabolic surgery (RYGB), they reported on one study that described decreased absorption of zinc and iron supplements three months following RYGB, and one study that showed no significant changes in pharmacokinetic properties (AUC0-24h, Cmax, and Tmax) six months following metabolic surgery.


“The data currently available in the literature is insufficient to support general recommendations, thus drug and supplement monitoring should be managed independently for each patient,” the authors concluded. “Bariatric surgery is a common therapeutic modality for individuals suffering from severe obesity and associated comorbidities. Because patients are often under long-term therapy, standardised studies are essential to ensure that they receive efficient and safe post-operative pharmaceutical management.”


The findings were reported in the paper, ‘Medication and supplement pharmacokinetic changes following bariatric surgery: A systematic review and meta-analysis’, published in Obesity Reviews. To access this paper, please click here


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