Effect of tildrakizumab (MK-3222), a high affinity, selective anti-IL23p19 monoclonal antibody, on cytochrome P450 metabolism in subjects with moderate to severe psoriasis.

AIMS: Tildrakizumab, an interleukin (IL)-23 inhibitor, is indicated for the treatment of moderate to severe chronic plaque psoriasis. Although tildrakizumab is not metabolized by, and does not alter, cytochrome P450 (CYP) expression in vitro, clinically significant pharmacokinetic effects through changes in systemic inflammation, which alters CYP metabolism, have been well documented. At the time of study conduct, the effect of modulation of inflammation/cytokines, including IL-23 inhibition with tildrakizumab, on CYP metabolism, and therefore the potential for disease-drug interactions, in psoriasis patients was unknown. We therefore assessed whether tildrakizumab alters CYP metabolism in subjects with moderate to severe psoriasis. METHODS: This was an open-label, fixed-sequence, two-period trial. In Period 1 (Day 1), subjects received an oral CYP probe cocktail of up to five drugs (midazolam 2 mg [3A4], caffeine 200 mg [1A2], warfarin 10 mg [2C9], omeprazole 40 mg [2C19] and dextromethorphan 30 mg [2D6]), followed by a 7-day washout. In Period 2, subjects received tildrakizumab 200 mg subcutaneously on Days 1 and 29 and a second CYP probe cocktail on Day 57. Substrate or metabolite pharmacokinetics, safety and changes in Psoriasis Severity Area Index (PASI), interleukin-6 (IL-6) and high-sensitivity C-reactive protein (hs-CRP), were assessed. RESULTS: Twenty subjects (13 men, 7 women) were enrolled. Tildrakizumab had no clinically relevant effect on the pharmacokinetics of any of the probe substrates tested. On Day 57 of Period 2, the median percentage decrease from baseline in PASI score following tildrakizumab was ~93%. There were no clinically relevant changes in IL-6 or hs-CRP. Treatment with tildrakizumab was generally well tolerated. CONCLUSION: In subjects with moderate to severe psoriasis, tildrakizumab 200 mg did not have a discernible effect on CYP metabolism. The potential for clinically significant drug-drug interactions (DDIs) with tildrakizumab in patients with psoriasis is low. The difference in the occurrence of DDIs seen with anti-inflammatory agents in rheumatoid arthritis patients compared with psoriasis patients may be due to the much greater extent of systemic inflammation in rheumatoid arthritis as compared to psoriasis.

Dysregulation of the mRNA Expression of Human Renal Drug Transporters by Proinflammatory Cytokines in Primary Human Proximal Tubular Epithelial Cells.

Proinflammatory cytokines, which are elevated during inflammation or infections, can affect drug pharmacokinetics (PK) due to the altered expression or activity of drug transporters and/or metabolizing enzymes. To date, such studies have focused on the effect of cytokines on the activity and/or mRNA expression of hepatic transporters and drug-metabolizing enzymes. However, many antibiotics and antivirals used to treat infections are cleared by renal transporters, including the basal organic cation transporter 2 (OCT2), organic anion transporters 1 and 3 (OAT1 and 3), the apical multidrug and toxin extrusion proteins 1 and 2-K (MATE1/2-K), and multidrug resistance-associated protein 2 and 4 (MRP2/4). Here, we determined the concentration-dependent effect of interleukin-6 (IL-6), IL-1ß, tumor necrosis factor (TNF)-α, and interferon-γ (IFN-γ) on the mRNA expression of human renal transporters in freshly isolated primary human renal proximal tubular epithelial cells (PTECs, n = 3-5). PTECs were exposed to either a cocktail of cytokines, each at 0.01, 0.1, 1, or 10 ng/mL or individually at the same concentrations. Exposure to the cytokine cocktail for 48 h was found to significantly downregulate the mRNA expression, in a concentration-dependent manner, of OCT2, the organic anion transporting polypeptides 4C1 (OATP4C1), OAT4, MATE2-K, P-glycoprotein (P-gp), and MRP2 and upregulate the mRNA expression of the organic cation/carnitine transporter 1 (OCTN1) and MRP3. OAT1 and OAT3 also appeared to be significantly downregulated but only at 0.1 and 10 ng/mL, respectively, without a clear concentration-dependent trend. Among the cytokines, IL-1ß appeared to be the most potent at down- and upregulating the mRNA expression of the transporters. Taken together, our results demonstrate for the first time that proinflammatory cytokines transcriptionally dysregulate renal drug transporters in PTECs. Such dysregulation could potentially translate into changes in transporter protein abundance or activity and alter renal transporter-mediated drug PK during inflammation or infections.

Clinical Usefulness of Drug-Disease Interaction Alerts from a Clinical Decision Support System, MedGuard, for Patient Safety: A Single Center Study.

Clinical decision support systems have been widely used in healthcare, yet few studies have concurrently measured the clinical effectiveness of CDSSs, and the appropriateness of alerts with physicians' response to alerts. We conducted a retrospective analysis of prescriptions caused disease-medication related alerts. Medication orders for outpatients' prescriptions, all aged group were included in this study. All the prescriptions were reviewed, and medication orders compared with a widely used medication reference (UpToDate) and other standard guidelines. We reviewed 1,409 CDS alerts (2.67% alert rate) on 52,654 prescriptions ordered during the study period. 545 (38.70%) of alerts were overridden. Override appropriateness was 2.20% overall. However, the rate of alert acceptance was higher, ranging from 11.11 to 92.86%. The MedGuard system had a lower overridden rate than other systems reported in previous studies. The acceptance rate of alerts by physicians was high. Moreover, false-positive rate was low. The MedGuard system has the potential to reduce alert fatigue and to minimize the risk of patient harm.

Disease-Drug Interactions Requiring Special Attention.

This short review addresses disease-drug interactions requiring special attention, namely interactions between common conditions and over-the-counter medication and interactions between rare conditions and drugs that are absolutely contraindicated. We specifically examine over-the-counter analgesics, antiemetics and drugs used to treat allergy symptoms and underlying disease conditions they can exacerbate. Resources for avoiding disease-drug interactions in patients with rare conditions, such as myasthenia gravis, glucose-6-phosphate deficiency, mitochondriopathies and long QT-syndrome are given. We also discuss methods for avoiding disease-drug interactions in clinical practice. These include awareness, regular diagnosis- and drug-history taking, consulting the product information, good communication between healthcare providers and patient education. Furthermore, pharmacovigilance activities help in the early identification and characterization of adverse drug reactions resulting from disease-drug interactions.

Influence of Inflammation on Cytochromes P450 Activity in Adults: A Systematic Review of the Literature.

Background: Available in-vitro and animal studies indicate that inflammation impacts cytochromes P450 (CYP) activity via multiple and complex transcriptional and post-transcriptional mechanisms, depending on the specific CYP isoforms and the nature of inflammation mediators. It is essential to review the current published data on the impact of inflammation on CYP activities in adults to support drug individualization based on comorbidities and diseases in clinical practice. Methods: This systematic review was conducted in PubMed through 7th January 2021 looking for articles that investigated the consequences of inflammation on CYP activities in adults. Information on the source of inflammation, victim drugs (and CYPs involved), effect of disease-drug interaction, number of subjects, and study design were extracted. Results: The search strategy identified 218 studies and case reports that met our inclusion criteria. These articles were divided into fourteen different sources of inflammation (such as infection, autoimmune diseases, cancer, therapies with immunomodulator…). The impact of inflammation on CYP activities appeared to be isoform-specific and dependent on the nature and severity of the underlying disease causing the inflammation. Some of these drug-disease interactions had a significant influence on drug pharmacokinetic parameters and on clinical management. For example, clozapine levels doubled with signs of toxicity during infections and the concentration ratio between clopidogrel's active metabolite and clopidogrel is 48-fold lower in critically ill patients. Infection and CYP3A were the most cited perpetrator of inflammation and the most studied CYP, respectively. Moreover, some data suggest that resolution of inflammation results in a return to baseline CYP activities. Conclusion: Convincing evidence shows that inflammation is a major factor to be taken into account in drug development and in clinical practice to avoid any efficacy or safety issues because inflammation modulates CYP activities and thus drug pharmacokinetics. The impact is different depending on the CYP isoform and the inflammatory disease considered. Moreover, resolution of inflammation appears to result in a normalization of CYP activity. However, some results are still equivocal and further investigations are thus needed.

Multi-factorial pharmacokinetic interactions: unraveling complexities in precision drug therapy.

Introduction: Precision drug therapy requires accounting for pertinent factors in pharmacokinetic (PK) inter-individual variability (i.e., pharmacogenetics, diseases, polypharmacy, and natural product use) that can cause sub-therapeutic or adverse effects. Although each of these individual factors can alter victim drug PK, multi-factorial interactions can cause additive, synergistic, or opposing effects. Determining the magnitude and direction of these complex multi-factorial effects requires understanding the rate-limiting redundant and/or sequential PK processes for each drug.Areas covered: Perturbations in drug-metabolizing enzymes and/or transporters are integral to single- and multi-factorial PK interactions. Examples of single factor PK interactions presented include gene-drug (pharmacogenetic), disease-drug, drug-drug, and natural product-drug interactions. Examples of multi-factorial PK interactions presented include drug-gene-drug, natural product-gene-drug, gene-gene-drug, disease-natural product-drug, and disease-gene-drug interactions. Clear interpretation of multi-factorial interactions can be complicated by study design, complexity in victim drug PK, and incomplete mechanistic understanding of victim drug PK.Expert opinion: Incorporation of complex multi-factorial PK interactions into precision drug therapy requires advances in clinical decision tools, intentional PK study designs, drug-metabolizing enzyme and transporter fractional contribution determinations, systems and computational approaches (e.g., physiologically-based pharmacokinetic modeling), and PK phenotyping of progressive diseases.

Therapeutic protein-drug interactions: plausible mechanisms and assessment strategies.

INTRODUCTION: Over the last three decades, therapeutic proteins have played an increasingly important role in pharmacotherapy. Owing to an expected significant increase in the coadministration of biotherapeutics with established pharmacotherapy regimens or even with other biotherapeutic agents, there is an increasing likelihood for the occurrence of clinically relevant drug interactions, so called therapeutic protein-drug interactions (TP-DIs). Areas covered: Our current understanding of TP-DIs and recent collaborations among industry, academia and regulatory agencies are reviewed in this article. Although most of the observed TP-DIs are mediated by disease states, immune status, and/or target physiology, TP-DI assessments are still done empirically. Plausible mechanisms of major TP-DIs involving therapeutic proteins (primarily monoclonal antibodies), either as victims or as perpetrators, are proposed, with mechanism-based strategies and assessment approaches to better evaluate their propensity are recommended. Expert opinion: Our current understanding of the mechanisms of TP-DIs is in its infancy. Much of the basic research needs to be conducted to verify existing TP-DI hypotheses or help predict and manage potential ones, whose efforts are not considered trivial and may be better achieved through close collaborations among scientists from academia, industry, and regulatory agencies.