**We're are delighted to announce that the new CMV DDI Manager has been added to our suite of leading DDI tools. It contains DDI Management recommendations for 7 CMV agents and approx. 1,000 co-medications.**

Patients diagnosed with cytomegalovirus (CMV) disease often have multiple comorbidities and are immunosuppressed, with polypharmacy being common.

Adding CMV treatment to already existing polypharmacy increases the risk of drug-drug interactions (DDIs). 

To counteract this risk, we announce the new CMV DDI Manager– a cutting-edge tool developed in partnership with leading experts in the field.

The novel anti-CMV agents letermovir and maribavir are also included in the new CMV DDI Manager. Both drugs have demonstrated clinical benefit in the prevention or treatment, respectively, of CMV infection in allogeneic haemopoietic stem cell transplant or solid organ transplant recipients. Letermovir and maribavir can be perpetrators and victims of drug-drug interactions.

_On April 28 at ECCMID in Barcelona, Laura Nijboer will be present with a poster about the management of drug-drug interactions with letermovir and maribavir DDIs with letermovir and maribavir. You are welcome to discuss this topic!_


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New: DDI Manager CMV!

From March 20 to 23, 2024, the European Lung Cancer Congress was held in Prague. 
David Burger presented a poster titled: ‘Development of an online tool for the management of drug-drug interactions between antithrombotic agents and the ROS1/TRK tyrosine kinase inhibitor repotrectinib’.  


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Drug-drug interactions between antithrombotic agents and repotrectinib

# The very latest updates on Drug-Drug Interactions hot off the presses


_How do you prevent adverse drug interactions in the rapidly evolving field of pharmacological therapies?_



Presented by **[Global DDI Solutions](https://www.global-ddi-solutions.org/)** in collaboration with Academic Medical Education, the DDI of the Month podcast brings you the latest updates on drug-drug interactions. Each month, a recent research paper will be selected and the author invited to discuss their findings, how to optimize DDI management and patient care going forward.

During the first podcast _Prof. Dr. David Burger_ will discuss with the author _Dr. Ditte Iversen_ the paper: [“Flucloxacillin is a weak inducer of CYP3A4 in healthy adults and 3D spheroid of primary human hepatocytes”](https://pubmed.ncbi.nlm.nih.gov/37235733/), published in Clinical Pharmacology & Pharmacotherapeutics in August 2023. 


Find out the interesting results of this study! **The podcast is available for you to hear now**: [DDI of the Month Podcast](https://academicmedicaleducation.com/ddi-month-podcast)


Flucloxacillin is an antibiotic widely used to treat infections and is normally used for around 10 days but can be used for 4-6 weeks depending on the infections. Nowadays, we know that flucloxacillin is an agonist of the nuclear receptor PXR, which regulates cytochrome P450 (CYP) 3A4, CYP2C9, CYP2C19 and CYP2B6. With this information, combining flucloxacillin with drugs that are substrates to these CYP enzymes may result in drug-drug interactions. Several studies show that flucloxacillin reduces warfarin efficacy and plasma concentrations of voriconazole, tacrolimus and repaglinide. However, the exact mechanism behind these interactions is unknown. 

The research group of Dr. Iversen has studied the extent of induction of flucloxacillin of the CYP enzymes (CYP3A4, CYP2C9, CYP2C19, CYP2D6, CYP1A2, and CYP2B6) in healthy adults and 3D spheroid of primary human hepatocytes (PHHs). The research group performed a randomized, unblinded, two-period, cross-over, clinical pharmacokinetic cocktail study with fourteen healthy adults. During the podcast, the [study](https://pubmed.ncbi.nlm.nih.gov/37235733/) will be discussed in detail. 


Go to the **[DDI Managers](https://ddimanager.co/)** to utilize the online resources designed to assist healthcare professionals in prescribing and enhancing overall quality of life for their patients. You can access a DDI manager for a specific disease and search for the related drugs from there.

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PODCAST: Flucloxacillin is a weak inducer of CYP3A4 by Dr. Iversen

Population aging is accompanied by a higher prevalence of comorbidities. For those comorbidities, different drugs are used, which leads to polypharmacy. With the use of many drugs, the risk of Drug-Drug interactions (DDIs) increases, which can cause treatment failure or undesired adverse effects. 

For certain patient groups (e.g. HIV or cancer patients) use of over-the-counter (OTC) drugs and other substances (e.g. vitamins/mineral supplements, anabolic steroids, recreational drugs) is increasingly common. These OTC drugs can also be perpetrators or victims of DDIs. Pharmacokinetic studies of OTC drugs combined with other drugs are limited. In addition, the use of OTC drugs is not always known to health professionals, which makes it difficult to collect and publish DDI cases with OTC drugs. 

Mainly, pharmacokinetic studies for registration of prescribed drugs are added to the product information of the drug. Case reports and studies from practice are minimally included in these documents. 

This study looked at reported cases of real-world DDIs on www.clinicalcasesDDIs.com between HIV medication and co-medication, including OTC drugs. This website is an open-access platform for healthcare professionals for concise descriptions of real-world clinical cases, specifically involving antiretrovirals and their associated clinical harms. 

Between March 2019 and May 2023, a total of 139 cases were reported, of which 27 cases with OTC. 11 cases with mineral supplements (calcium and magnesium) were reported, 8 cases with herbals, 4 cases with weight loss drugs, 3 cases with anabolic steroids and 1 case with recreational drug (MDMA). Of these cases, 21 cases had unwanted outcomes (78%). 17 cases of cases with unwanted outcomes had a loss of ARV efficacy, defined as detectable plasma HIV-RNA previously virologically suppressed individuals. In these cases, 10 cases of mineral supplements were involved, primarily calcium and magnesium. 

It is often underestimated how much impact mineral supplements can have on prescribed medication. Therefore, it is important to educate patients about potential interactions with OTC drugs, as many individuals may not perceive minerals, herbal supplements, recreational drugs, or other OTC drugs as traditional medications and they may not be aware of possible DDIs. 

19.4% of the cases involved OTC drugs which means that in addition to ARVs, this may also be a common problem with other drugs, such as cancer medications, antibiotics and antifungal agents. Therefore, it is important to document real-world cases to bridge knowledge gaps and increase the quality of care. 
20.
For the databases of the DDI Manager, real-world outcomes of DDIs are examined, including articles and case reports. This allows a complete picture of potential DDIs per drug.

**See for more information the article:** [Outcomes of Drug Interactions Between Antiretrovirals and Co-Medications, Including Over-the-Counter Drugs: A Real-World Study](https://pubmed.ncbi.nlm.nih.gov/38372897/)


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Drug-drug interactions with Over-the-Counter drugs

Organic cation transporter 2 (OCT2) and multidrug and toxin extrusion proteins 1 and 2 (MATE1/2) are major drug secretion systems. Predicting the involvement of these transporters in the metabolization pathway and the effect of new drugs on these transporters often involves in-vitro studies. The results of the in-vitro studies determine the need for in vivo studies for this specific pathway by extrapolation. Current guidelines recommend considering setting up an in-vivo drug-drug interaction (DDI) study when the maximal unbound plasma concentration / half-maximal inhibitory concentration (Imax,u/IC50) value is greater than the regulatory agency's cutoff value (e.g. ≥ 0.1 for OCT2 or MATE1 by FDA).

It remains a challenge to make a good prediction of what the effect may be in vivo based on in-vitro data. The drug has to be located in the filtrate (intracellular) to affect these transporters. Currently, a prediction is made for DDIs via OCT2/MATE1 transporters in vivo with Imax,u/IC50, which is measured in plasma. This can be one of the reasons for false- or over-prediction of OCT2/MATE-mediated DDIs. 
Vieira et al. explored a new in vitro tool, a double-transfected system, for DDI risk assessment related to OCT2/MATE1 transporters. Metformin is a commonly used drug excreted by OCT2/MATE1 transporters and is used as an indicator to measure the effect of other drugs (hydroxychloroquine, brigatinib, cimetidine, famotidine, pyrimethamine) on OCT2/MATE1 transporters. 

First, the inhibitory effect of all drugs was studied in trans wells. They showed all MATE1 or OCT2 inhibition. Then, the effects were studied in a double-transfected system, due to the studying the inhibition effect in filtrate. Hydrochloroquine and brigatinib did not show inhibition on the MATE1 transporter in the double-transfected system, because these two drugs were not transported to the filtrate. 

Famotidine, cimetidine and pyrimethamine did have an inhibitory effect on OCT2 transporters in a double-transfected system. With the use of Imax,u/IC50, all three compounds should be studied in vivo for potential DDIs. In contrast, only cimetidine and pyrimethamine should be studied for potential DDIs in vivo with this new method and famotidine not. These results correspond to the practice of monitoring interactions with cimetidine and pyrimethamine with OCT2 substrates and not for famotidine.

Optimizing in-vitro research to avoid unnecessary research and costs of in-vivo research for possible DDIs is important. It is known that OCT2/MATE1 transporters often have limited influence on DDIs, but this new method can make a better prediction of whether a new drug has an influence on these transporters and to what extent the influence is.


_See for more information the article_: [Use of a Double-Transfected System to Predict hOCT2hMATE1-mediated Renal Drug-drug Interactions](https://pubmed.ncbi.nlm.nih.gov/38326034/)



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New method prediction renal drug-drug interactions in vivo related to renal OCT2/MATE1 transporters

In 2022, more than 2 million cases of lung cancer were recorded, making it the second most prolific cancer in the world. 

We are delighted to announce the first P**harmacological Optimization of Lung Cancer Treatment Webinar - Drug-Drug Interactions, Therapeutic Drug Monitoring, and Immunotherapy** will take place on **22 April 2024**.

Non-small lung cancer (NSCLC) is the most common type of lung cancer, with first-line treatment consisting of small molecule inhibitors (SMIs) and immune/chemotherapy.
 
With advent of these novel therapies, several pharmacological issues have arisen that need full attention of clinicians, pharmacists and clinical researchers.

**The following topics will be discussed during the webinar:**

**- Drug-Drug Interactions between SMIs and Directly-Acting Oral Anti-coagulants (DOACs) in Patients with Lung Cancer**

**- Therapeutic Drug Monitoring (TDM) of Small Molecule Inhibitors in Patients with Lung Cancer: Ready for the Clinic?**

**- Management of toxicities from immunotherapy: an ESMO Clinical Practice Guideline**

![20-03-2024 speakers.jpg](https://ddi.ams3.digitaloceanspaces.com/20_03_2024_speakers_a9023ac425.jpg)

This webinar is an exciting opportunity for many healthcare professionals – including pulmonologists, medical oncologists, nurse specialists, pharmacists, and clinical pharmacologists – to increase their knowledge about the pharmacological optimization of lung cancer treatment.

_For more information and registration see_: [Pharmacological Optimization of Lung Cancer Treatment Webinar: Drug-Drug Interactions, Therapeutic Drug Monitoring, and Immunotherapy | AME (academicmedicaleducation.com)](https://academicmedicaleducation.com/meeting/pharmacological-optimization-lung-cancer-treatment-webinar-drug-drug-interactions)


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WEBINAR: Pharmacological Optimization of Lung Cancer Treatment Webinar

The Lung Cancer DDI Manager is expanded with a new drug: **Repotrectinib**!
U.S. Food & Drug Administration approved repotrectinib on November 15, 2023 and the EMA on February 1, 2024. 

Repotrectinib is an addition to the treatment for ROS1 TKI-naïve and -pretreated adult patients with ROS1-positive locally advanced or metastatic NSCLC and TKI-naïve and -pretreated adult and pediatric patients 12 years and older with NTRK-positive locally advanced or metastatic solid tumors. 

Repotrectinib is metabolized by CYP3A4 enzymes and, in vitro, a substrate of P-gp transporter. Also, repotrectinib is a perpetrator of drug-drug interactions (DDIs) due to the moderate inducing effect on CYP3A enzymes. Therefore, repotrectinib has an increased risk of DDIs. 

The product information has included some results of DDI studies: 
- Coadministration with itraconazole (strong CYP3A4&P-gp inhibitor) increased repotrectinib AUC and Cmax by 5.9-fold and 1.7-fold, respectively.
- Coadministration with rifampin (strong CYP3A4 & P-gp inducer) decreased repotrectinib AUC and Cmax by 92% and 79%, respectively.
- Repotrectinib (moderate CYP3A inducer) decreased midazolam (CYP3A4 substrate)  AUC by 69% and midazolam Cmax by 48%.

In addition, many more drugs are metabolized by CYP3A enzymes or induce of inhibit CYP3A4. In the product information is not a complete overview of these drugs. Therefore, we made extrapolations based on the results above for an overview of clinically relevant DDIs with repotrectinib. 

For more information about possible DDIs with repotrectinib: Dr. David Burger will attend ELCC (March 20-23, 2024 in Prague) with a poster presentation on the relevant DDIs of repotrectinib with antithrombotic agents. 

And make sure to take a look at the Lung Cancer DDI Manager for all clinical relevant DDIs with repotrectinib!


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New drug added to the Lung Cancer DDI Manager!

The ESMO 2023 (European Society for Medical Oncology) was held in Madrid, Spain. Specialists, oncologists, pharmacists, students came together to share knowledge about oncology. In this post interesting presentations about drug-drug management in patients with cancer are summarized. 

**Frequency and clinical relevance of drug-drug interactions with oxycodone among patients with cancer**

*L. Hulskotte, et al.*

Oxycodone is commonly used in patients with cancer and is metabolized by cytochrome P (CYP) 3A4 enzymes. Therefore, oxycodone is common a victim of drug-drug interactions (DDIs). Oxycodone combined by CYP3A4 inducer could result in loss of efficacy and combined with CYP3A4 inhibitor in adverse drug reactions. The frequency and pharmacological and clinical relevance of DDIs between oxycodone and perpetrators were studied in patients with cancer.

A cross-sectional study was performed between 1 September 2021 and 1 September 2022 in Deventer hospital. Pharmacy records were used to study concomitant use of oxycodone and DDI perpetrators and the frequency of multiple interactions. These perpetrators were determined from Lexicomp®, Micromedex®, the Dutch Kennisbank® and Dutch Commentaren Medicatiebewaking®. The relevance of the identified perpetrators were examined by a clinical pharmacologist and a medical oncologist. 

254 records with oxycodone use were found. In 227 records, at least 1 clinically relevant perpetrator was found. Of these, 210 were clinically relevant. In total, 80 perpetrators were identified, with 65 (81.3%) being considered clinically relevant. In 21 (8.3%) records with oxycodone use, interactions were observed. The Dutch compendia generally classified DDIs with oxycodone as less relevant than Lexicomp and Micromedex. 

In conclusion, a high frequency of pharmacological and clinical relevant perpetrators of DDIs and double interactions with oxycodone were observed. To improve the pharmacovigilance, drug interaction compendia used in Dutch healthcare should be revised in according international drug compendia. 

**Personalised dosing of oral targeted therapies in oncology: The era of therapeutic drug monitoring**

*M.B.A. van der Kleij, et al.*

Oral targeted therapy in oncology is common given in standard fixed dose to patients. The high interpatient variability in pharmacokinetics (PK), may result in overdosing or underdosing causing toxicity or loss of efficacy. In addition, oral targeted therapies, such as abiraterone, imatinib, sunitinib and pazopanib, have increased risk of drug-drug interactions (DDIs), due to metabolism by or influence on cytochrome P (CYP) enzymes or transporters. These DDIs have influence on the blood concentrations of these drugs. Personalised dosing through therapeutic drug monitoring may optimize treatment outcome. 

This study is an ongoing research, what is focused on feasibility, efficacy, and tolerability of TDM of several oral targeted therapies. PK-values are collected 4-8-12 weeks after initiating oral targeted therapy and every 12 weeks thereafter. Based on efficacy target and measured concentration in patients, recommendations are given to reach the target efficacy. Examples of recommendations are dose adjustment, intake with food, split of intake moments, emphasize compliance and adjustment of interacting medication. An intervention is successful when PK-level is above target and no dose limiting toxicity within one month took place. 

41.3% (n=378) of 916 evaluable patients had all PK-levels above target, while 58.7% (n=538) had ≥1 PK–level below target. PK-guided intervention was possible in 55.4% (n=298) and was successful for 38.3% of patients below target. The total patients above PK-level targets increased to 63.8%, a gain of 22.5%. 

In conclusion, TDM can be useful to optimize treatment with oral targeted therapies. Before TDM implementation in the practice, TDM should be more evaluated for these therapies. For this, established exposure-response and -toxicity relationships are required.  When TDM will be standard of care for oral targeted therapies, it can also be used for DDI management. 


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ESMO October 20-24, 2023; Madrid Spain

During ID Week in Boston we launched the Fungal infections DDI Manager! In addition, we attended several presentations during this congress. In this meeting report, a couple of interesting presentations are summarized.

**Pharmacokinetic Analysis of Co-Administering Doravirine, Tenofovir Disoproxil Fumarate, Estradiol, and Spironolactone**

*Lam et al.*

This study is a two-way drug interaction trial between combination of doravirine, lamivudine and tenoforvir disoproxil fumarate (DOR/3TC/TDF) and estradiol and spironolactone in transgender women (man-to-woman). The aim was to research the effect of DOR/3TC/TDF on the pharmacokinetics of estradiol and spironolactone and vice versa. In addition, the safety and tolerability of the drug combination was defined with adverse effects. The effect of coadministration of DOR/3TC/TDF and estradiol and spironolactone on the testosterone concentrations was also determined. 

The results shows no clinically significant interactions between DOR/3TC/TDF and estradiol and spironolactone in transgender women. The log paired difference (90% CI) of the AUC of DOR, TDF and estradiol were -0.03%, 0.15% and -0.03%, respectively.

Also, the combination of DOR/3TC/TDF and estradiol and spironolactone is safe and tolerable to use. Mild adverse events in intensity were observed, which were not related to the study interventions, and these were resolved before the end of the trial without additional action.  
The concentration of testosterone was not changed by adding estradiol and spironolactone to the treatment with DOR/3TC/TDF. 

In conclusion, the combination of DOR/3TC/TDF with estradiol and spironolactone in transgender women can used safely. 

**The Impact of Rifampicin on Blood Pressure in Patients Receiving Nifedipine: A Retrospective Study**

*Eljaady et al.*

In this retrospective study, the effect of rifampicin on the systolic blood pressure (SBP) in patients who use nifedipine was researched in King Abdulaziz University Hospital. Rifampicin and nifedipine is a known DDI, due to induction of CYP3A4 by rifampicin and nifedipine is metabolized by CYP3A4. The effect of rifampicin on SBP is unknown. 

Patients >18 years old with treatment of nifedipine were included. Patients with uncontrolled hypertension (>140 mmHg baseline SBP) and betablockers in use were excluded from the study. The treatment of rifampicin was initiated on day 1. The study outcomes were the change of SBP on day 1 to 8 compared to baseline. 

16 patients were included in this study. The median maximum increase in SBP after starting rifampicin was 24 mmHg. The median SBP from day 2 to 8 are shown in the table. From day 3 with rifampicin the change in SBP was significant and clinically relevant. 

DAY 	 SYSTOLIC BLOOD PRESSURE (MMHG)

2	       135 [128.5-141.5] (P=0.147)

3	       146.5 [140.5-154.25] (P=0.002)

4	       142.5 [132.75-160.5] (P=0.009)

5	       149.5 [136-159.75] (P=0.005)

6	       146.5 [134.25-159.5] (P=0.012)

7	       149 [143.25-154.5] (p=0.007)

8	       151.5 [143.75-163] (P=0.007)


In conclusion, rifampicin is associated with a significant and clinically relevant increase in SBP. To prevent increases in SBP, it is important for patients using nifedipine to substitute temporarily to another class of antihypertensive medications when rifampicin is initiated. 


 


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ID Week October 11-15, 2023; Boston USA

The edition of TIMM 2023 was held in Athens Greece. A couple of interesting presentations about drug-drug interactions (DDIs) are summarized in this post. 

**Potential drug-drug interactions of antifungal prophylaxis and midostaurin in FLT3-mutated acute myeloid leukemia – clinical implications of therapeutic drug monitoring**

*Joisten et al.*

The aim of this study is to determine the clinical relevance of the drug-drug interaction (DDI) between midostaurin and posaconazole. Midostaurin is a FLT3-inhibitor (inhibitor of a cytokinereceptor in the liver) and used in treatment of acute myeloid leukemia. It is metabolized by CYP3A4 and is therefore a potential victim of a DDI. Posaconazole is used in these patients for prophylaxis of invasive fungal disease and is a strong inhibitor of CYP3A4. 

In this study, blood trough concentrations of midostaurin and posaconazole and occurred adverse reactions were determined. From 24 patients twice-weekly trough concentrations were measured. A greater inter- and intra-variability was found ranged from <0.01 mg/l to 24.5 mg/l for midostaurin and from <30 µg/l to 2571 µg/l for posaconazole, respectively. Five patients had excessively high midostaurin concentrations over 15 mg/L.

In addition, exanthema was determined as possible related adverse event of midostaurin toxicity and prolonged QTc interval, perimyocarditis, hyperbilirubinemia/liver cell necrosis, diarrhea and nausea were determined as probably related adverse event. Which can be explained by the high concentrations of midostaurin. 

In conclusion, midostaurin and posaconazole is a clinical relevant DDI. Therapeutic drug monitoring can be used for decision-making dose adjustment of both drugs and reducing toxicity of midostaurin. 

**Physiological-based pharmacokinetic analysis of drug–drug interactions between isavuconazole and vincristine in pediatric subjects**

*Choules et al.*

In this study, the influence of isavuconazole on vincristine is researched in pediatric cancer population. Vincristine is used for treatment of leukemia in pediatric. Secondary, fungal infections are common in this patient population. These infections are treated with isavuconazole. Known is that isavuconazole is a moderate inhibitor of CYP3A4, inducer of CYP2B6 and potential inhibitor of P-gp and OCT-2 transporter. On the other hand, vincristine is metabolized by CYP3A4 and excreted in biliary by P-gp. The combination of isavuconazole and vincristine is potential for a DDI. 

A PBPK model for isavuconazole and vincristine in pediatric cancer population was built in Simcyp©. This model can predict the vincristine exposure when coadministered with isavuconazole. The dose regimen started with a loading dose of isavuconazole. After 12 hours the maintenance dose regimen of isavuconazole daily was given. Vincristine was coadministered at day 5. This model predicted a geometric mean AUC ratio of vincristine coadministered with isavuconazole ranged from 1.54- to 1.69-fold depending on the dosing scheme. The largest magnitude of DDI was predicted when a dose of 372 mg of isavuconazole was administered. No effect was predicted on the geometric mean of Cmax ratio. 

In conclusion, isavuconazole is a weak inhibitor when coadministered with vincristine in pediatric cancer population. A slight increase in vincristine exposure can be expected when vincristine is coadministered with isavuconazole. 


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TIMM October 20-23, 2023

The management  of  drug–drug  interactions  (DDIs) is a key component of product labels approved by regulatory authorities such as the US Food and Drug Administration (FDA) or the European Medicines Agency (EMA). Based on the product information (PI), both healthcare professionals (HCPs, for individual patients) and content developers responsible for the maintenance of clinical decision support (CDS) systems (on a population level) assess the DDI potential when a new drug is prescribed in patients that use other medications. When there is no recommendation for DDI management for a specific co-medication in the PI, extrapolation based on information from general clinical pharmacology principles can be needed for the drugs of interest, to prevent toxicity or a lack of efficacy.
Unfortunately, there are large gaps between the actual information in the PI and potentially relevant DDIs. Typically, only a small minority of potential co-medications is listed in the PI, which results in HCPs either ignoring  potential  DDIs  or  undertaking individual DDI assessments for the non-listed co- medications. This leads to variability in how extrapolations are applied, both for individual patients and in the DDI databases that are compiled in CDS systems. Moreover, although some HCPs will undertake these assessments correctly, for example, by consulting online DDI resources, many will not or will rely entirely on the PI, which may lead to patient harm. It can be argued that providing  a  vast  list  of  potential  DDIs in a label may be unrealistic, but as the PI is a legal document that then serves as a source of information provided in other resources, including CDS systems, we feel that it is important to highlight some of these issues, and through multi-stakeholder discussions, arrive at a consensus that is both consistent with good medical practice and allows the rationalization of prescribing by individual clinicians to maximize benefits and reduce harms.

To illustrate our concerns, we have used the newly published PI of the novel human immunodeficiency virus type 1 (HIV-1) capsid inhibitor lenacapavir (Sunlenca) as an exemplar.(1,2) We have assessed the (in)completeness of the PI, and how we should perform our extrapolations to define potential DDIs. Although we have focused on DDI management in the care of people living with HIV, we feel that the principles we highlight apply to many other therapeutic areas.

**Lenacapavir**

Similar to other antiretrovirals, lenacapavir has an extensive DDI profile, and instructions for DDI management can be found in the PI published  by  the EMA and the FDA.(1,2) Lenacapavir is a substrate for cytochrome P450, family 3, subfamily A (CYP3A), P- glycoprotein 1 (P-gp), and uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1), and hence can be a victim of a DDI with inducers or inhibitors of these pathways. In addition, lenacapavir is a moderate CYP3A inhibitor and can thus also be a perpetrator of a DDI when combined with CYP3A substrates.

We evaluated the extent to which the DDI management information included in the PI would help us when we are consulted for a potential DDI in a patient about to start treatment with lenacapavir. Despite the potential impact on patient outcomes, to our knowledge, no coordinated efforts have yet been made to optimize DDI management information to guide HCPs.

![Tabel 1.PNG](https://ddi.ams3.digitaloceanspaces.com/Tabel_1_36004e4e25.PNG)

**Lenacapavir as a Potential Victim of a DDI: Inducers**

As lenacapavir is a substrate for CYP3A, P-gp, and UGT1A1, the PI states that administration in combination with strong inducers is contraindicated, and its use is not recommended with moderate inducers (Table 1). The agents in this category studied in formal DDI studies were rifampicin and efavirenz as representatives of a strong and a moderate inducer, respectively. Coadministration with rifampicin led to an 84% and 55% reduction in the area under the plot of plasma concentration versus time after dosage (AUC) and maximum serum concentration (Cmax) of lenacapavir, respectively, and to a 56% and 36% reduction in lenacapavir AUC and Cmax with the coadministration of efavirenz. Such reductions in lenacapavir exposure would be clinically important, with the potential to lead to virological failure.
However, surprisingly, a number of agents listed on the FDA website as being strong CYP3A inducers are not listed in the lenacapavir PI as contraindicated medications (see Table 1)(3), including apalutamide, enzalutamide, ivosidenib, lumacaftor, and mitotane. Similarly, there is no mention of the moderate CYP3A inducers bosentan, cenobamate, dabrafenib, etravirine, lorlatinib, pexidartinib, primidone, and sotorasib. The current EMA guidelines on the investigation of drug interactions does not provide a table with relevant CYP3A inducers (4), so no comparison could be made.

There is a risk that the incomplete list of compounds that potentially perpetrate DDIs with lenacapavir in the PI, and the discrepancies between the PI from different regulators, may lead to confusion for HCPs. The incorrect and/or inconsistent management of DDIs may have potentially significant consequences for the efficacy of lenacapavir in individual patients. We recommend the development of a consensus list of inducers, including a mechanism to update that system; product labels could refer to this consensus list.

**Lenacapavir as a Potential Victim of a DDI: Inhibitors**

In the PI, the coadministration of combined P-gp, UGT1A1, and strong CYP3A inhibitors with lenacapavir is not recommended. This is based on a formal DDI study with atazanavir/cobicistat, a combination that indeed inhibits all 3 pathways, leading to a substantial increase in lenacapavir AUC and Cmax (with a geometric mean ratio 6.60 and 4.21, respectively). The potential safety issues of such overexposure to lenacapavir are unknown.

Although we acknowledge that we are not aware of any drug other than atazanavir/cobicistat that has a combined inhibitory activity on CYP3A, P-gp, and UGT1A1 pathways, it is likely that some patients living with HIV are treated with a combination of drugs that together  will  result  in  the  inhibition  of all 3 pathways, for instance combined treatment with darunavir/cobicistat (inhibitors of CYP3A and P-gp) and tyrosine kinase inhibitors such as sorafenib and regorafenib (inhibitors of UGT1A1). A warning that addresses this possibility is currently missing in the product labels. This also highlights the fact that with the increasing prevalence of polypharmacy, we need to consider not only the 2-way drug interactions but also those involving 3, 4, or more drugs.

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**Lenacapavir as a Potential Perpetrator of a DDI: CYP3A/P-gp Substrates with a Narrow Therapeutic Range**

The FDA product label warns of the potential risk of adverse reactions when lenacapavir, a moderate CYP3A inhibitor, is combined with drugs primarily metabolized by CYP3A. There is a reference to “sensitive CYP3A substrates” in the FDA PI of lenacapavir. The EMA PI uses slightly different language and cautions the use of “sensitive CYP3A substrates with a narrow therapeutic index”. Clearly, the question that follows from this is which agents fall into this category? The CYP3A substrates described in the drug interaction tables in the PI for lenacapavir are listed in Table 2.

Although Table 2 shows an inconsistency between the  PI  documents  from  the  2  regulatory  agencies in the listing of CYP3A substrates that cannot be combined with lenacapavir, we feel that there are 2 other more fundamental issues that need to be considered:

- What is the procedure for selecting these agents amongst the large number of known CYP3A sub- strates? The FDA website hosts a table listing sensitive substrates,3 and for CYP3A there are 2 lists: one of CYP3A substrates with 10-fold increase in AUC with the coadministration of strong inhibitors, and another where a 5- to 10-fold increase in AUC is expected. Lenacapavir is not a strong but a moderate CYP3A inhibitor. Only a subset of these CYP3A substrates with a narrow therapeutic range are specified in the lenacapavir product label, with relevant agents, such as colchicine, ibrutinib, tacrolimus, vincristine, etc., missing.

- For DDI management when lenacapavir is coprescribed with direct oral anticoagulants (DOACs), there is a reference in the PI for DOACs on how to dose them with moderate CYP3A/P-gp inhibitors. However, we do not understand why there is no specific recommendation in the lenacapavir PI regarding DOACs? Such inconsistencies in the DDI management for some drugs in the respective PI documents may lead to errors and requires additional efforts by HCPs to adequately deal with DDIs.
 
Suboptimal DDI Information in Product Labels: Is There a Problem?

The PI labels published when a drug is licensed are legal documents agreed between the manufacturing authorization holder and the regulatory agency, and are written to assist HCPs in prescribing medicine rationally to maximize the benefit–harm ratio. HCPs should thus be able to use the information from the PI, combine it with the characteristics of  the individual patient, and make a benefit/risk assessment. Developers of DDI databases included in CDS systems use the information in the PI to populate their system when a new drug comes to the market.

As illustrated with lenacapavir, we are concerned that the interpretation of DDI information from the PI, both on an individual and a software system level, may result in substantial variability in the handling of DDIs across the world. Not surprisingly, when comparing the guidance on DDI management from 3 major online drug information resources, Kontsioti et al found the level of consistency to be 10.65%-18.32%, with significant variability in categorizing the severity of DDIs and the clinical advice given.(5) They conclude: “Such variability in information could have deleterious consequences for patient safety.” This is supported by many reports of the increased risk of adverse reactions where DDI management failed in preventing adverse clinical outcomes (6–11), and by many case reports. So yes, in short, there is a problem.

**Optimized DDI Management in the Future: We Need a Solution**

Although we are not the first group to raise this issue (12), to the best our knowledge there are no coordinated actions with all stakeholders (pharma companies, regulatory authorities, clinical societies, and academia) to improve the information provided for the management of DDIs. We call for the development of a consortium to optimize DDI management and welcome your suggestions. A tentative agenda for such a consortium is presented in Box 1.

*Box 1. Agenda for Optimized DDI Management*

- •	Consensus documents for the assessment of DDI potential (substrates, inhibitors, and inducers) and for the extrapolation of the DDI potential to other drugs
- •	What is the use of physiologically based pharmacokinetic (PBPK) modeling to fill the DDI knowledge gap?
- •	Construction of complete DDI datasets for all available medications based on clinical data and PBPK simulations in the absence of other studies
- •	Consideration of more complex DDI scenarios going beyond the 2-way interactions to include interactions involving more than 2 drugs
- •	Consideration of drug–drug–gene interactions
- •	Consideration of comorbidities
- •	Guidance document for manufacturers on how to construct drug interaction tables
- •	Harmonization of drug interaction tables
- •	Guidance for uptake in CDS systems
- •	Identify research gaps
- •	Acknowledgement of therapeutic ranges in the label to facilitate pharmacokinetically guided dosing
- •	Development of educational materials to improve DDI management among prescribers


We do not underestimate the challenges and pitfalls in implementing this framework. But if all stakeholders acknowledge the problem, and are motivated to support this endeavor, we should be able to make a start. We need to think of novel ways of providing up-to-date PI to prescribers, for example by using electronic methods, which can then be used as the ultimate source of truth that can be used by secondary sources such as CDS systems. Hopefully, this commentary is a start. It is incumbent upon all of  us to maximize the benefits of medications for our patients and to minimize the harms.


**_References_**
1.	EMA. Sunlenca. Summary  of  Product  Characteristics 2022.	Available	from:	https://www.ema.europa.eu/en/ documents/product-information/sunlenca-epar-product- information_en.pdf
2.	FDA. Sunlenca. Prescribing Information. 2022 Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/ 215973s000lbl.pdf
3.	FDA. Drug Development and  Drug  Interactions  |  Table of Substrates, Inhibitors and Inducer 2022 Available from: https://www.fda.gov/drugs/drug-interactions-labeling/drug- development-and-drug-interactions-table-substrates- inhibitors-and-inducers#table3-3
4.	EMA. Guideline on the investigation of drug interactions 2012. Available  from.     https://www.ema.europa.eu/en/documents/ scientific-guideline/guideline-investigation-drug-interactions- revision-1_en.pdf
5.	Kontsioti E, Maskell S, Bensalem A, Dutta B, Pirmohamed
M. Similarity and consistency assessment of three major on- line drug-drug interaction resources. Br J Clin Pharmacol. 2022;88(9):4067-4079.
6.	Gronich  N,  Stein  N,  Muszkat   M.   Association   between use of pharmacokinetic-interacting drugs  and  effectiveness and safety of direct acting oral anticoagulants: nested case-control study. Clin Pharmacol Ther. 2021;110(6):1526- 1536.
7.	Cid A, Smetana ME, Hebert C, Coe K, Smith JM. Impact of concomitant fluconazole on direct oral anticoagulant bleeding risk. Pharmacotherapy. 2022;42(12):880-9.
8.	Wei N, Zheng B, Que W, Zhang J, Liu M. The association between proton pump inhibitor use and systemic anti-tumour therapy on survival outcomes in patients with advanced non- small cell lung cancer: A systematic review and meta-analysis. Br J Clin Pharmacol. 2022;88(7):3052-3063.
9.	Honda T, Abe K, Oda M, et al. Gastrointestinal bleeding during direct oral anticoagulant therapy in patients with nonvalvular atrial fibrillation and risk of polypharmacy. J Clin Pharmacol. 2022;62(12):1548-1556.
10.	Turner RM, de Koning EM, Fontana V, Thompson A, Pirmohamed M. Multimorbidity, polypharmacy, and drug- drug-gene interactions following a non-ST elevation acute coro- nary syndrome: analysis of a multicentre observational study. BMC Med. 2020;18(1):367.
11.	Grymonprez M, Vanspranghe K, Capiau A, Boussery K, Steurbaut S, Lahousse L. Impact of P-glycoprotein and/or CYP3A4-interacting drugs on effectiveness and safety of non- vitamin K antagonist oral anticoagulants  in  patients  with atrial fibrillation: a meta-analysis. Br J Clin Pharmacol. 2022;88(7):3039-3051.
12.	Scheife RT, Hines LE, Boyce RD, et al. Consensus recom- mendations for systematic evaluation of drug-drug interaction evidence for clinical decision support. Drug Saf. 2015;38(2):197- 206.



_Published article_: [What the Product Label Does Not Tell You About Drug-Drug Interaction Management: Time for a Re-Appraisal](https://pubmed.ncbi.nlm.nih.gov/37477172/)


Sunlenca1.jpg

What the Product Label Does Not Tell You About Drug–Drug Interaction Management; Time for a Re-Appraisal

Triazole antifungal agents (fluconazole, isavuconazole, itravuconazole, posaconazole and voriconazole) are used in practice for prevention and treatment of invasive fungal infections. Due to the variable pharmacokinetics and known drug-drug interactions (DDIs), the use of these drugs in practice is complicated. Therefore, therapeutic drug monitoring (TDM) is commonly recommended to monitor drug concentrations. The results of a recent large multi-center study in America shows that in approximately half of patients receiving posaconazole or voriconazole TDM  was performed, despite these recommendations. McCreary et al. has summarized some utilities of the Society of Infectious Diseases Pharmacists to emphasize TDM use during treatment with triazole antifungal agents. The utilities described in the article are indication, PK considerations, sample (parent drug and/or metabolites), timing sample, type is assay, target concentrations, toxic concentrations, PD targets and recommendations for dose adjustments. Below the indication for TDM and dose adjustment recommendation per antifungal agent is explained, due this applies to DDI management with azoles. For itraconazole, voricanozole, and posaconazole, TDM should be routinely employed during prophylaxis or treatment and especially with a dose adjustment or new comedication with a drug-drug interaction. TDM is recommended for fluconazole and isavuconazole in specific circumstances. 

The advice for **itraconazole** is to perform TDM when capsules (prophylaxis and treatment) and suspension or SUBA-itraconazole capsule (prophylaxis) are used and consider TDM for suspension or SUBA-itraconazole capsule when used for treatment. When a dose adjustment is required, an increment between 50 and 100 mg can be chosen.

TDM for **posaconazole** is recommended for immediate-release suspension (prophylaxis or treatment) and direct release tablet, suspension or intravenous (prophylaxis) and consider  TDM for direct release tablet, suspension or intravenous (treatment). For direct release tablet increments of 100 mg can be performed. 

TDM should be routinely employed for prophylaxis and treatment with **voriconazole**, due to intra- and inter-patient pharmacokinetic variability with dosing and the association of toxicity. Dose adjustment can be made with the help of dosing algorithms Bayesian software. 

TDM for **fluconazole** is uncommon, but can be considered in special populations with concern for treatment failure, such as pediatric patients, patients with reduced absorption and patients receiving continuous renal replacement therapy. Dose increments of 200 mg can be performed for intravenous and oral fluconazole.

The specific circumstances for TDM for **isavuconazole** concentrations are for patients receiving alternative methods of administrations (e.g. via enteral feeding tubes, opened capsules), critical illness, extremes of weight, refractory infections, pediatric, drug-drug interactions or other factors that alter pharmacokinetics. For intravenous or oral isavuconazole, dose increments of 186 mg  can be performed (186 mg isavuconazonium sulfate = 100 mg isavuconazole).

**Link to full article**: [Utility of triazole antifungal therapeutic drug monitoring: Insights from the Society of Infectious Diseases Pharmacists - McCreary - 2023](https://accpjournals.onlinelibrary.wiley.com/doi/full/10.1002/phar.2850)



Utility of triazole antifungal therapeutic drug monitoring

The DDI Manager Fungal Infections has been expanded with a new drug rezafungin. 

It is approved by the FDA and EMA since March and December 2023, respectively. Rezafungin is indicated for the treatment of invasive candidiasis in adults. In the United States, rezafungin is also indicated for candidemia and only for use in patients with limited or no alternative options of treatment. The interaction profile is limited because metabolism do not involve enzymes. No effect of rezafungin was seen on enzymes during clinical studies. 

See for more information the article about the clinical studies with several drugs (e.g. midazolam, ciclosporin, digoxin): [Flanagan et al; 2023](https://pubmed.ncbi.nlm.nih.gov/37154682/).
