The scale of the investigation is striking. The researchers extracted 12,763 adverse event reports involving riociguat from the United States Food and Drug Administration’s Adverse Event Reporting System, known as FAERS, and a further 17,316 reports from VigiAccess, the World Health Organization’s public gateway to global pharmacovigilance data. Together these databases capture hundreds of thousands of reports submitted by healthcare professionals, patients, and manufacturers across dozens of countries, offering a view of drug safety that no single trial can match. Women accounted for the majority of reports in both databases, a pattern consistent with the epidemiology of pulmonary hypertension, which disproportionately affects women, but also a finding that would prove consequential when the team examined sex-specific reactions.

At the heart of the analysis lies a statistical technique called disproportionality analysis, the workhorse of modern pharmacovigilance. Rather than simply counting how often a reaction appears, disproportionality methods ask whether a particular drug-event pair occurs together more often than would be expected by chance, given the overall composition of the database. The team applied multiple established algorithms, including the reporting odds ratio, the proportional reporting ratio, and Bayesian confidence propagation methods, each with defined thresholds for what constitutes a meaningful signal. Requiring agreement across several independent algorithms reduces the risk that a single statistical quirk will be mistaken for a genuine safety concern, a persistent problem in spontaneous reporting data where reporting biases and confounding abound.

The results largely vindicated the drug’s known safety profile. The most frequently reported adverse events were dyspnoea, the medical term for breathlessness, and hypotension, or abnormally low blood pressure. Both are biologically plausible for riociguat: the drug works by enhancing the nitric oxide signalling pathway, relaxing blood vessels and lowering pulmonary vascular resistance, so systemic vasodilation and its consequences are expected effects pushed to an uncomfortable extreme in some patients. The strongest statistical signals included diastolic hypotension and bendopnoea, a subtle symptom in which breathlessness occurs while bending over, such as when putting on shoes. Bendopnoea is increasingly recognized as an early marker of worsening cardiac function, and its emergence as a signal suggests clinicians are documenting it more systematically in this patient population.

The sex-stratified analysis produced some of the study’s most clinically actionable findings. After adjusting for age and body weight, two variables that could otherwise explain differences in drug exposure and metabolism, female patients reported significantly more dyspnoea, headache, nausea, vomiting, and chest pain than male patients. Such gender differences in adverse drug reactions are an area of growing scientific interest, driven by known variations in body composition, hormonal influences, renal and hepatic clearance, and even the historical underrepresentation of women in pivotal trials. For riociguat, the pattern implies that women may need closer monitoring during dose titration, particularly for gastrointestinal intolerance and blood pressure-related symptoms, and that prescribers should not assume trial-derived tolerability data apply uniformly across sexes.

Drug-drug interaction analysis added a second layer of concern. The team identified 30 interaction signals, and the companies of riociguat proved telling: endothelin receptor antagonists accounted for 36.67 percent of the signals and oral anticoagulants for 33.33 percent. Both drug classes are staples of pulmonary hypertension care, meaning the interactions are not exotic edge cases but routine combinations encountered in everyday practice. Endothelin receptor antagonists and riociguat both affect vascular tone, raising questions about additive haemodynamic effects, while anticoagulants are standard in chronic thromboembolic disease and interact with any drug that influences bleeding risk or hepatic metabolism. The authors used multiple signal-detection algorithms for the interaction analysis as well, and their supplementary tables transparently flag which signals were supported by only a single method, an unusually honest approach to the uncertainty inherent in this kind of data mining.

Timing proved to be another revealing dimension. The median time to onset of adverse events was 225 days, with an interquartile range spanning from 47 days to just over 710 days. This long and widely distributed onset window carries a sobering implication: riociguat toxicity is not confined to the initiation period that trials and early monitoring tend to emphasize. A substantial fraction of reactions emerge months or even years into therapy, precisely when patients and clinicians have settled into a sense of security. Sustained vigilance, rather than a brief introductory monitoring burst, appears to be what the data demand, and the late-onset pattern also complicates causal attribution, since comorbid disease progression can mimic drug effects in this progressive illness.

Crucially, the team did not stop at database mining. They cross-validated their pharmacovigilance signals against the safety data from six riociguat clinical trials, finding general concordance between the real-world reports and the trial evidence for established concerns such as hypotension, gastrointestinal disorders, and peripheral edema. But the databases also yielded signals that trials had not flagged, most notably traumatic fractures and pain in the jaw. Traumatic fractures could plausibly reflect falls precipitated by dizziness or syncope from hypotension, an indirect but clinically important chain of harm, while jaw pain raises questions that will require targeted follow-up. These discrepancies illustrate the complementary nature of the two evidence systems: trials establish causation with rigor but limited statistical power for rare events, while spontaneous reports detect rare and unexpected events but cannot by themselves prove causation.

The practical culmination of the study is a pharmacist-led management framework built on the narrative evidence review and the pharmacovigilance findings. The workflow is organized into three phases: pre-treatment evaluation, treatment initiation, and maintenance, with six core responsibilities assigned to pharmacists. These are drug interaction management, safety signal recognition, patient education, efficacy and safety assessment, professional documentation, and quality indicators. The framework reflects a broader shift in hospital practice, in which pharmacists move from dispensing roles into direct therapeutic management, particularly for high-risk medications like riociguat that demand blood pressure monitoring, careful titration, and constant attention to a patient’s full medication list. Given that the interaction signals cluster around drugs pulmonary hypertension patients take routinely, the pharmacist’s cross-checking role becomes not a luxury but a structural safeguard.

The study carries the usual caveats of spontaneous reporting research. FAERS and VigiAccess suffer from underreporting, inconsistent reporting quality, missing denominators that make incidence rates impossible to calculate, and the reporting biases that come with media attention and litigation. The authors were careful to frame their findings as signals warranting attention rather than proven causal effects, and the ethics declarations note that the use of publicly available, anonymized data required no institutional review board approval. Still, the convergence of evidence from two independent global databases, agreement across multiple statistical algorithms, and validation against six clinical trials gives these findings a weight that single-database studies often lack. For the growing population of patients living with pulmonary hypertension, the message is one of informed vigilance: riociguat remains a valuable therapy, but its safety profile is broader, later-emerging, and more sex-dependent than the label alone suggests, and the pharmacist may be the most important person watching for what the label does not say.

Subject of Research: Post-marketing safety evaluation of the pulmonary hypertension drug riociguat using FAERS and VigiAccess pharmacovigilance databases

Article Title: Safety evaluation of riociguat: insights from FAERS and VigiAccess databases, and establishment of pharmacist management framework

Article References: Hong, X., Guo, C., Wang, H., Cai, H., & Zhao, S. (2026). Safety evaluation of riociguat: insights from FAERS and VigiAccess databases, and establishment of pharmacist management framework. BMC Pharmacology and Toxicology. https://doi.org/10.1186/s40360-026-01245-6

Image Credits: AI Generated

DOI: 10.1186/s40360-026-01245-6

Keywords: riociguat, pharmacovigilance, FAERS, VigiAccess, adverse events, pulmonary hypertension, drug-drug interactions, hypotension, pharmacist-led management, drug safety, gender differences, disproportionality analysis

The review, led by Lotte M.G. Hulskotte and colleagues in the Netherlands, systematically searched PubMed and Embase for evidence on drug–drug and food–drug interactions and pharmacodynamic adverse effects of all thirty SMIs approved by the US Food and Drug Administration and the European Medicines Agency for non-small cell lung cancer, from long-standing agents such as erlotinib and crizotinib to newcomers including zongertinib, sevabertinib and sunvozertinib. The searches, initiated in October 2025 and finalised in July 2026, were supplemented with regulatory documents from both agencies, and the authors applied a pragmatic hierarchy of evidence ranking pharmacokinetic studies and meta-analyses above phase 1/2 trials, observational data, label information and expert opinion.

At the heart of the pharmacokinetic problem lies chemistry. Most SMIs are weakly basic, lipophilic molecules whose absorption depends delicately on the acidity of the stomach. When acid-reducing agents such as proton pump inhibitors raise gastric pH, the drugs shift toward a less soluble, non-ionised form that dissolves poorly, cutting systemic exposure. The magnitude is striking: selpercatinib exposure fell by roughly 70 percent when omeprazole was given in the fasted state, and sotorasib lost 57 percent of its exposure with omeprazole even when taken with food. Erlotinib, co-administered with esomeprazole, lost nearly half its area under the curve. Bioequivalence standards allow exposure to vary only within 80 to 125 percent of the reference value, so deviations of this size translate directly into subtherapeutic concentrations, lost efficacy and, ultimately, disease progression.

Liver enzymes provide the second major axis of interaction. Most SMIs are metabolised primarily by cytochrome P450 iso-enzymes, above all CYP3A, so potent inducers such as rifampicin can collapse drug levels while inhibitors such as itraconazole can push them to toxic heights. Rifampicin cut adagrasib exposure by 95 percent, while itraconazole raised repotrectinib exposure nearly sevenfold. Compounding the problem, several agents are themselves auto-inducers or auto-inhibitors of CYP enzymes — dabrafenib, encorafenib, lorlatinib and osimertinib induce their own clearance, while adagrasib, ceritinib and taletrectinib inhibit it — meaning that single-dose interaction studies may not predict steady-state behaviour. Transporters such as P-glycoprotein and breast cancer resistance protein add further complexity, although their intestinal contribution is generally considered minor.

Food, by contrast, can be an ally. High-fat meals delay gastric emptying, increase bile flow and create a lipophilic environment that enhances solubilisation of many of these drugs. Alectinib is the poster child: a high-fat meal raised its systemic exposure by roughly 230 to 250 percent, and a clinical crossover study showed that 35 percent of patients failed to reach the alectinib exposure threshold when taking the drug with low-fat yoghurt, compared with only 5 percent eating a continental breakfast or lunch. This very property has been exploited therapeutically — ceritinib’s approved dose fell from 750 mg fasted to 450 mg with food after feeding studies showed comparable exposure with less gastrointestinal toxicity, and the FDA has required a post-marketing evaluation of taletrectinib dosing with food for the same reason. Food also reduced inter-individual variability for several agents, improving predictability of therapeutic exposure.

The interplay between food and acid suppression, however, is drug-specific and sometimes counterintuitive. Selpercatinib’s PPI-induced exposure loss is largely rescued by co-administration with a meal. Sotorasib behaves in the opposite way, losing even more exposure when food and a PPI are combined. For erlotinib, an acidic glass of cola partially reversed the damage done by esomeprazole, restoring roughly 40 percent of lost exposure. The authors conclude that when PPI use is unavoidable, clinicians should weigh the individual pharmacokinetics of each SMI, considering food co-administration, acidic beverages or staggered dosing as mitigation strategies.

Turning to the drugs’ intrinsic toxicities, the review paints a landscape where class effects mask considerable agent-to-agent variation. Corrected QT interval prolongation, which can degenerate into dangerous arrhythmias, affects the entire class but is most pronounced with adagrasib, ceritinib, crizotinib, encorafenib, osimertinib and taletrectinib, with median increases exceeding ten milliseconds and the highest rates of clinically significant prolongation seen with adagrasib, encorafenib, taletrectinib, entrectinib and selpercatinib. Because the effect is largely exposure-dependent, any interaction that raises drug levels also raises arrhythmia risk. Others, including alectinib, gefitinib, capmatinib and the newer HER2 inhibitors, showed no clinically meaningful QTc changes. Management centres on electrocardiographic monitoring, correction of concomitant QT-prolonging factors, and dose interruption or discontinuation when the QTc exceeds 500 milliseconds.

Pneumonitis, the non-infectious inflammation of lung tissue that can prove fatal, occurs with most SMIs but clusters around particular agents. Brigatinib carried the highest trial incidence at 9 percent of all-grade events, with an unusual early onset within the first week — the rationale for its mandatory one-week 90 mg lead-in dose before escalation. Pralsetinib affected about 12 percent of patients including one fatal case, while adagrasib, capmatinib, ensartinib and sunvozertinib each produced events in 5 to 6 percent. Strikingly, ethnicity emerged as an independent risk factor: all-grade interstitial lung disease was reported in up to 15 percent of Japanese patients on gefitinib and 17 percent on osimertinib. Rechallenge after pneumonitis remains fraught — one real-world study found a 50 percent twelve-month recurrence rate when patients were rechallenged with osimertinib itself, versus 15 percent with alternative EGFR inhibitors.

Among the quieter but increasingly recognised toxicities is weight gain. NTRK inhibitors cause weight gain in 53 percent of patients, likely through on-target inhibition of TRKB, a hypothalamic receptor governing appetite, with entrectinib reaching roughly 66 percent incidence. Among ALK inhibitors, lorlatinib produced all-grade weight gain in up to 81 percent of patients, with grade 3 events in up to 23 percent and a median gain of 4.5 kilograms in a prospective study; alectinib added an average 9 centimetres of waist circumference over a year. The irony is acute for alectinib, whose absorption depends on high-fat meals. Management spans lifestyle counselling, systematic weight monitoring and, where needed, GLP-1 receptor agonists — though even here caution is warranted, as semaglutide was recently shown to reduce alectinib exposure by 32 percent.

Further distinguishing the class, EGFR inhibitors uniquely damage the ocular surface — keratitis in 1 to 3 percent of patients and conjunctivitis up to 24 percent with dacomitinib — because EGFR sustains corneal epithelium and tear production, while BRAF/MEK combinations bring uveitis and retinal pigment epithelial detachment, the latter affecting roughly 30 percent of patients on encorafenib plus binimetinib. Central neurotoxicity, including cognitive disorders in up to a third of patients on capmatinib, entrectinib, lorlatinib and repotrectinib, peripheral neuropathy in up to 44 percent on lorlatinib, dabrafenib-driven pyrexia in 39 percent of combination-treated patients, severe stomatitis with second-generation EGFR inhibitors, and hepatotoxicity necessitating intra-class switches — erlotinib after gefitinib injury, adagrasib after sotorasib injury — complete the picture. The authors’ overarching message is that safe prescribing of these transformative drugs demands equal attention to what patients eat, what else they swallow, and which specific molecule sits in the capsule: pharmacokinetic–pharmacodynamic associations remain under-studied, and filling that gap could enable personalised dosing that maximises efficacy while sparing patients avoidable harm.

Subject of Research: Pharmacokinetic and pharmacodynamic considerations for prescribing small molecule kinase inhibitors in non-small cell lung cancer

Article Title: Pharmacological considerations for prescribing of small molecule inhibitors in patients with non-small cell lung cancer

Article References: Hulskotte, L. M., Veerman, G. M., Lanser, D. A., Reyners, A. K., van Schaik, R. H., Dingemans, A.-M. C., Taxis, K., Mathijssen, R. H., & Jansman, F. G. (2026). Pharmacological considerations for prescribing of small molecule inhibitors in patients with non-small cell lung cancer. eClinicalMedicine, 100, Article 104199. https://doi.org/10.1016/j.eclinm.2026.104199

Image Credits: AI Generated

DOI: 10.1016/j.eclinm.2026.104199

Keywords: non-small cell lung cancer, small molecule inhibitors, drug-drug interactions, pharmacokinetics, CYP3A, proton pump inhibitors, food-drug interactions, QTc prolongation, pneumonitis, weight gain, ocular toxicity, targeted therapy