Can methylphenidate be given to patients after gastric bypass? Is absorption affected?

Background

The impact of drug absorption after weight loss is dependent on the type of gastric surgery. Techniques such as sleeve gastrectomy, in which approximately 80% of the stomach is removed, and gastric banding, in which an obstructive band is placed around the proximal stomach are primarily restrictive procedures. Roux-en-Y gastric bypass (RYGB) is the most common type of gastric bypass and is characterized by a small functional pouch at the top of the stomach, which is isolated from the rest of the stomach and directly connected to the jejunum, allowing food to bypass most of the stomach and the entire duodenum. This procedure is likely to cause malabsorption. [1]

Limited data guide dose adjustments of medications after bariatric surgery. A RYGB bypasses the duodenum, proximal jejunum, and all of the stomach except the cardia; drug absorption is proposed to be affected because medications pass into the cardia and are not exposed to gastric acid. It is suggested that RYGB surgeries often lead to weight loss, which can also affect the volume of distribution of fat-soluble medications. Methylphenidate is water-soluble. [2], [3]

Psychiatric medications are common for patients with gastric bypass. The wall of the duodenum that may be bypassed includes CYP isozymes CYP1A2, CYP3A4, CYP3A5, and CYP2D6 which play a role in drug metabolism for many psychiatric agents. As methylphenidate is primarily metabolized by de-esterification, this is of less concern. [3], [4]

A study replicated a physiologic-based absorption model to depict the pharmacokinetic profile of oral extended-release methylphenidate products. The authors concluded that immediate-release formulation dissolved quickly in the gastrointestinal fluid in the stomach and that a majority of absorption occurs in the jejunum, which is the proximal part of the small intestines. [4]

Relevant Prescribing Information

Metabolism and Excretion

In humans, methylphenidate is metabolized primarily by de-esterification to PPAA, which has little or no pharmacologic activity. In adults the metabolism of methylphenidate hydrochloride extended-release tablets once daily as evaluated by metabolism to PPAA is similar to that of methylphenidate three times daily. The metabolism of single and repeated once-daily doses of methylphenidate hydrochloride extended-release tablets is similar.

After oral dosing of radiolabeled methylphenidate in humans, about 90% of the radioactivity was recovered in urine. The main urinary metabolite was PPAA, accounting for approximately 80% of the dose.

Food Effects

In patients, there were no differences in either the pharmacokinetics or the pharmacodynamic performance of methylphenidate hydrochloride extended-release tablets when administered after a high-fat breakfast. There is no evidence of dose dumping in the presence or absence of food.

Alcohol Effect

An in vitro study was conducted to explore the effect of alcohol on the release characteristics of methylphenidate from the methylphenidate hydrochloride 18 mg extended-release tablets dosage form. At an alcohol concentration up to 40% there was no increased release of methylphenidate in the first hour. The results with the 18 mg tablet strength are considered representative of the other available tablet strengths.

Special Populations

Gender

In healthy adults, the mean dose-adjusted AUC(0-inf) values for methylphenidate hydrochloride extended-release tablets were 36.7 ng•h/mL in men and 37.1 ng•h/mL in women, with no differences noted between the two groups.

Race

In adults receiving methylphenidate hydrochloride extended-release tablets, dose-adjusted AUC(0-inf) was consistent across ethnic groups; however, the sample size may have been insufficient to detect ethnic variations in pharmacokinetics.

Age

Increase in age resulted in increased apparent oral clearance (CL/F) (58% increase in adolescents compared to children). Some of these differences could be explained by body-weight differences among these populations. This suggests that subjects with higher body weight may have lower exposures of total methylphenidate at similar doses.

The pharmacokinetics of methylphenidate hydrochloride extended-release tablets has not been studied in children less than 6 years of age.

Renal Insufficiency

There is no experience with the use of methylphenidate hydrochloride extended-release tablets in patients with renal insufficiency. After oral administration of radiolabeled methylphenidate in humans, methylphenidate was extensively metabolized and approximately 80% of the radioactivity was excreted in the urine in the form of PPAA. Since renal clearance is not an important route of methylphenidate clearance, renal insufficiency is expected to have little effect on the pharmacokinetics of methylphenidate hydrochloride extended-release tablets.

Hepatic Insufficiency

There is no experience with the use of methylphenidate hydrochloride extended-release tablets in patients with hepatic insufficiency.

Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

How does gastric bypass impact methylphenidate? Should methylphenidate be prescribed for patients having gastric bypass?

Please see Tables 1-2 for your response.

Methylphenidate Toxicity After Roux-en-Y Gastric Bypass
Design	Case Report
Case Presentation	A 40-year-old man with morbid obesity (300 lbs; BMI 41 kg/m²) with a history of type 2 diabetes and ADHD underwent laparoscopic Roux-en-Y gastric bypass in April 2014. Before the procedure, the patient was on methylphenidate 54 mg in the morning and 36 mg at lunch and was well maintained. Two weeks post-procedure, the patient asked for a consultation at the psychiatric emergency department because of insomnia and symptoms of stress. Sleeping pills were prescribed, but the methylphenidate dose was left unaltered. A few days later the patient presented with auditory hallucinations, paranoid thoughts and was very nervous and agitated. The total weight loss after the procedure was, at that point, 37.5 pounds, 12.5%, representing an excess BMI loss of 31%. 20 days post-operation the patient discontinued methylphenidate. Two weeks after discontinuation, ADHD-associated symptoms returned although his previous hallucinations and paranoid thoughts had stopped. Over the next several months the patient was prescribed Atomoxetine will little effect. In November 2014 the patient was placed on methylphenidate 18 mg every morning in conjunction with psychologist treatment. On April 15th, the patient was back on his original dose, and in May of the same year, the patient reported improvement in functioning regarding his ADHD symptoms without any of the symptoms of insomnia, anxiety, or paranoia.
Adverse Events	Auditory hallucinations, anxiousness, insomnia, and stress.
Study Author Conclusions	A patient on medication for ADHD had well-known neuropsychiatric symptoms of methylphenidate toxicity within 2 weeks after LRYGB when using the same dose of CNS stimulant after LRYGB as previous to the surgery.
InpharmD Researcher Critique	Given this case report, monitoring methylphenidate should be considered, especially after surgery. At the time of this paper's publication, no studies had evaluated serum concentrations of methylphenidate after LRYGB; however, a paper did study the dissolution of common psychiatric medications, studied in an RYGB in vitro model. This paper found methylphenidate to dissolve slightly more in the RYGB model (80 mg dissolved vs 70 mg in the control setting), but this was not statistically significant. A number of factors after LRYGB might affect the pharmacokinetics. Changes in transit time and acidity as well as other factors have to be taken into consideration when discussing why previous therapeutic doses may contribute to drug toxicity.

References:

Ludvigson M, Haenni A. Methylphenidate toxicity after Roux-en-Y gastric bypass. Surg Obes Relat Dis. 2016;12(5):e55-e57. doi:10.1016/j.soard.2016.03.015

Impaired oral absorption of methylphenidate following Roux-en-Y gastric bypass
Design	Case Report
Case Presentation	A 52-year-old morbid obese patient with diagnosed ADHD, was well maintained on methylphenidate for 2 years. Two weeks after the RYGB surgery the patient started experiencing very short effect of the medication and started gradually increasing doses and changing formulations to try to achieve the same effect. Changing the dosage form from immediate-release to slow-release product, as well as dose increase, failed to recover the therapeutic effects of the drug to the pre-surgery level. Among formulations that were tried were methylphenidate syrup, long-acting capsules, opened long-acting capsules with contents swallowed, and immediate-release formulations. He reported no effect at all with the extended-release formulation (Concerta®) and ~1-hour effect with the long-acting formulation (Ritalin® LA). At 1.5 years post-surgery he was taking 40 mg up to 5 times per day with a reported effect that lasted up to ~1 hour after each dose. At the consultation, the patient reported no side effects from using the methylphenidate except the effect of wearing-off. The patient was prescribed a methylphenidate patch (Daytrana®) with additional doses of immediate-release tablets as needed. The patient reported great improvement in effect with the patch lasting ~10 hours. The patient needed no additional doses of immediate-release methylphenidate tablets while using the patch. Eventually, the patient suffered rash and pruritis that were not tolerated nor improved with changing the area of the patch and was then moved back to the immediate release methylphenidate formulation. None of these effects of the short duration of methylphenidate action and the need for high doses were felt after the gastric band procedure.
Adverse Events	Rash, puritis (transdermal patch)
Study Author Conclusions	This case suggests that bariatric surgeries may alter the absorption of orally administered methylphenidate in an unpredictable manner; hence, it is prudent to closely monitor the therapeutic/toxic effects of methylphenidate following bariatric surgery and to be aware of non-oral treatment options of this medication.
InpharmD Researcher Critique	After bypass surgery, this patient had decreased effect of the medication. Monitoring for subtherapeutic response or toxicities is needed. Exploring dose adjustment or formulation changes may be warranted in this population. Several mechanisms may lead to absorption alterations of orally administered drugs following bariatric surgery, involving each and every step of the drug absorption cascade. Disintegration and deaggregation of the solid matrix to form small particles may be hampered by the small gastric volume and the impaired motility of the stomach after bariatric surgery. Pre-systemic metabolism of methylphenidate may lead to unpredictable changes in systemic levels of the medication after bariatric surgery. Intestinal expression of different enzymes may be asymmetrical throughout the GI tract and bypassing the upper small intestinal region may allow a greater fraction of the drug dose to escape pre-systemic intestinal metabolism and overall higher bioavailability if the circumvented intestinal segment is rich in the relevant enzymes. Since this patient re-experienced therapeutic effects after switching from PO to patch formulation, there may be major GI anatomical/physiological changes after the surgery on the oral absorption and bioavailability of methylphenidate.

References:

Azran C, Langguth P, Dahan A. Impaired oral absorption of methylphenidate after Roux-en-Y gastric bypass. Surg Obes Relat Dis. 2017;13(7):1245-1247. doi:10.1016/j.soard.2017.03.003