key: cord-0771274-1d2bg55c
authors: Bojdani, Ermal
title: Pharmacokinetic implications leading to marked valproic acid level-drop during COVID-19 treatment
date: 2020-12-31
journal: Psychiatry Res
DOI: 10.1016/j.psychres.2020.113701
sha: 184b8be2cb987d611f82a24e4595d184400a0452
doc_id: 771274
cord_uid: 1d2bg55c

nan

We recently noticed a marked valproic acid level-drop in one of our patients with Bipolar disorder being treated for COVID-19, despite no change to his valproic acid dosage, and wanted to report and educate our fellow colleagues on the new challenges that the COVID-19 infection and treatment present to the reliability of reading, interpreting, and taking action on a valproic acid level.

Our patient, who gave permission for this work to be published (some identifying information changed), was an 86 year old man, divorced, with a past psychiatric history of Bipolar I disorder not on any psychotropic medications, alcohol use disorder, cocaine use disorder, and tobacco use disorder (50 pack/year, last use five years ago), a past medical history of coronary artery disease, congestive heart failure (last echocardiogram ejection fraction 55%), atrial fibrillation not on anticoagulation due to falls, sick sinus syndrome status post permanent pace maker implantation, hypertension, hearing loss, stage I renal cell carcinoma status post left partial nephrectomy, who presented to the emergency department from home for ongoing shortness of breath for three days, with symptoms associated with orthopnea and cough productive of gray sputum. In the ED, he was afebrile (T 97.0), HR 85, RR 17, BP 140/63, saturating 92% on room air. Labs were notable for a positive COVID-19 test, troponin was elevated at 0.17, BNP 175, Ddimer 408, ESR 18, CRP 64.5, LDH 290, ferritin 356, procalcitonin 0.11. Chest x-ray showed bilateral lower lung hazy opacities and mild interval worsening of pulmonary vascular congestion. The patient received a DuoNeb, furosemide 40mg IV, and was started on remdesivir and dexathemasone. He was placed on BiPAP at a rate of 10, 30% FiO2 after increased work of breathing was noticed.

The patient was admitted to the intensive care unit due to Covid-19 pneumonia and hypoxic respiratory failure, and then after initial stabilization (initiated on azithromycin, ceftriaxone, continued on dexamethasone and remdesivir infusions, and initiated on Seroquel 25mg by mouth daily) transferred to the general medical floor for ongoing medical treatment, including of bipolar disorder (history of treatment with Lithium 600 mg po BID for at least a decade until 2015 and since then on no psychotropics) and delirium with behavioral disturbance (eventually placed on dexmedetomidine gtt for agitation) which had been managed with low dose seroquel prior. A rapid response code was called 4 days after admission for respiratory failure (despite being on O2 via NC at 6L/min) and difficulty swallowing, and the patient was subsequently re-transferred to the intensive care unit, placed on BiPAP, and psychiatry consultation was requested for ongoing management of agitation at which time PRN IMs of haloperidol and lorazepam were recommended. Nutrition consult 5 days after admission recommended continuing NPO-Enteral Tubefeeding (po diet when appropriate), via NGT, continuous x 24 hours, full, Peptamen Intense VHP formula, with goal rate of 70mL/hr, and free water flushes of 30mL q1h via automatic pump infusion which provides an additional 720mL daily; there was a goal rate of 1680 kcals, 155gPro, & 2131 mL's free water daily. Six days after admission he was started on valproic acid solution (Baller et  al., 2020) and quickly up titrated by day 8 to 500mg/10mL ng q12h, with trough level at 10 days after admission of 44 ug/mL and was intubated for mechanical ventilation due to worsening hypoxia on the same day. Since this level, additional changes to his medication regimen included initiation of additional infusions (fentanyl, propofol), and his weight gain through the hospital course had been attributed to fluid retention ( ). When the valproic acid level was re-checked on day 14 of admission, it was surprisingly <10 ug/mL despite the patient continuing to receive his usual dosage of 500mg/10mL ng q12h. A drug-drug interaction calculator from UpToDate was used to assess for metabolism induction (valproate is a minor substrate of CYP2A6, CYP2B6, CYP2C19, CYP2C9, and CYP2E1) and whether certain drugs could have lowered the level (the patient's regimen throughout the hospital stay has included insulin glargine and aspart, metoprolol, furosemide, quetiapine, hydralazine, isosorbide mononitrate, polyethylene glycol, latanoprost, tamsulosin, finasteride, allopurinol, aspirin, digoxin, enoxaparin, ipratropium, albuterol, fentanyl, propofol, dexmedetomidine, azithromycin, ceftriaxone, dexamethasone and remdesivir), however no culprit drug was identified and in fact salicylates (aspirin) could increase valproate levels with the recommendation to monitor therapy closely; his liver and kidney laboratory values had consistently been unremarkable. Since both of his valproic acid lab results continued to be subtherapeutic for bipolar treatment including agitation, a recommendation was made to increase valproic acid to 750 mg ng q12h and to check next VPA level in 5 days if hepatic function continued stable, otherwise sooner, with goal of at least 60-80 ug/mL, noting that it was hard to make sense of what the laboratory value means given the various changes in the patient's body processes due to COVID-19 and its treatment.

As shown by this case, body parameters that are condition dependent (ex: due to COVID-19 infection pneumonia and treatment, including use of NG tube and intravenous infusions) like volumes (intra/extracellular), circulation and cerebral blood flow, or blood/tissue pH, affect pharmacokinetics (absorption, distribution, metabolism, excretion), and it's likely that this complex interaction resulted in marked valproic acid level-drop in this patient. More data are needed to better understand how COVID-19 infection and treatment affect drug levels, like that of valproic acid, and further on how to interpret these levels in a meaningful way in order to make sound and safe treatment decisions in conjunction with monitoring the patient's clinical picture. 

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