Dose selection for investigations of intrinsic and extrinsic factors of pharmacokinetic variability as well as safety is a challenging question in the early clinical stage of drug development. The dose of an investigational product is chosen considering the compound information available to date, feasibility of the assessments, regulatory requirements, and the intent to maximize information for later regulatory submission. This review selected 37 programs as case examples of recently approved drugs to explore the doses selected with focus on studies of drug interaction, renal and hepatic impairment, food effect and concentration-QTc assessment.The review found that regulatory agencies may consider alternative approaches if justified and safe as illustrated in these examples. It is thus recommendable to use the first in human trial as an opportunity to assess QT-prolongation and drug interactions using probes or endogenous markers while maximizing the DDI potential, increasing sensitivity and ensuring safety. Early understanding of dose proportionality assists dose finding and simple and fast to conduct DDI study designs are advantageous. Single dose impairment studies despite non-proportional/time-dependent PK are often acceptability.Overall, the early understanding of the drug\'s safety profile is essential to ensure the safety of doses selected while preventing clinical trials with unnecessary exposure when using high doses or multiple doses. The information collected in this retrospective survey is a good reminder to tailor the early clinical program to the profile and needs of the molecule and consider regulatory opportunities to streamline the development path.

Elderberry flower extract is marketed as an herbal supplement with purported benefits in boosting the immune system. The use of elderberry increased during the coronavirus pandemic. However, the interaction of elderberry with cytotoxic medicines has remained elusive. Pazopanib is a multikinase inhibitor approved for patients diagnosed with soft-tissue sarcoma. The present study reported on the case of a middle-aged woman diagnosed with localized intermediate-grade sarcoma of the left sartorius muscle who received neoadjuvant pazopanib with radiation therapy. The patient had no other medical comorbidities and only took over-the-counter (OTC) elderberry supplements for numerous years to \'boost\' her immune system. She started pazopanib at 400 mg per os (PO) daily, which was increased to 800 mg PO daily after a week. By week three on pazopanib, the patient reported intense nausea and a number of loose stools, requiring anti-nausea medication. By the fourth week on pazopanib, laboratory tests showed grade 3 liver injury, as demonstrated by a fivefold rise in liver enzymes along with severe nausea and loose stools. All medications, including elderberry supplement, were stopped. Within two weeks of stopping all medicines, the liver enzymes started normalizing within two weeks and were normal by the end of four weeks. Pazopanib treatment was resumed without the recurrence of side effect. Pazopanib is metabolized in the liver via the cytochrome P 450 (CYP)3A4 enzyme pathway. Hence, potent inhibitors of CYP3A4 are avoided for concurrent use with pazopanib. Small in vitro studies on elderberry extracts have shown weak inhibition of CYP3A4. However, considering the wide usage of elderberry and the availability of mixed supplements OTC, it is essential to pursue clinical studies in cancer patients to understand the interactions of elderberry extracts with cytotoxic medicines. In this report, the scientific evidence behind the use of elderberry was reviewed and a hypothesis of its interaction with pazopanib was proposed.

Carbamazepine remains a first-line antiepileptic medication for the treatment of partial seizures. Despite its widespread use, carbamazepine has significant neurotoxicity and hypersensitivity reactions. We report a case of a patient post-kidney transplant who was on regular carbamazepine for childhood epilepsy and developed nystagmus, diplopia and a broad-base gait after receiving diltiazem. Understanding of the interaction between diltiazem and carbamazepine is necessary to prevent the neurotoxic effects.

BACKGROUND: Many of the drugs used for the treatment and alleviation of symptoms in cancer patients are known to inhibit or induce cytochrome P450 (CYP). Therefore, it is important to pay attention to the drug interactions of opioid analgesics that are metabolized by CYPs, because for example when using oxycodone metabolized by CYP3A4, it is possible that the effect will be attenuated or enhanced by the concomitant use of drugs that induce or inhibit CYP3A4. Aprepitant, an antiemetic drug used in many patients receiving anticancer drugs, is known as a moderate competitive inhibitor of CYP3A4. We experienced a case of respiratory depression caused by opioids, which was suspected to be caused by a drug interaction with antiemetics especially aprepitant.
METHODS: The patient was a 72-year-old man. He had been treated with continuous oxycodone infusion for perianal pain associated with the rectal invasion of prostate cancer. No comorbidities other than renal dysfunction were observed. Oxycodone treatment was started at 48 mg/day, and was increased to 108 mg/day, and then the pain decreased. Once the pain was controlled, chemotherapy was planned. Antiemetics (dexamethasone, palonosetron, and aprepitant) were administered before anticancer drug administration. Approximately 3 hours after antiemetics administration and before the administration of the anticancer drugs, a ward nurse noticed that oversedation and respiratory depression had occurred. When the patient was called, he immediately woke up and was able to talk normally, so the anticancer drugs were administered as scheduled. About 2 hours after the nurse noticed oversedation, the attending physician reduced the dose of oxycodone infusion to 48 mg/day. After that, his drowsiness persisted, but his respiratory condition improved. Despite reducing the dose of oxycodone to less than half, the pain remained stable at numeric rating scale (NRS) 0-1, without the use of a rescue dose. The patient was discharged from the hospital 36 days after the administration of anticancer drugs, without any problems.
CONCLUSIONS: The cause of respiratory depression in this case was thought to be a combination of factors, including drug interactions between oxycodone and antiemetics, and oxycodone accumulation due to renal dysfunction.

BACKGROUND: Coronavirus disease 2019 (COVID-19) infection in lung transplant recipients can be lethal owing to the use of immunosuppressants. Antiviral agents may be administered to these patients. Co-packaged nirmatrelvir-ritonavir is a new agent currently being used in combination.
METHODS: In this report, we present a case of a 64-year-old woman, a lung transplant recipient, who experienced hyponatremia and showed a high serum tacrolimus concentration following the administration of the co-packaged nirmatrelvir-ritonavir combination.
CONCLUSIONS: Although the nirmatrelvir-ritonavir and tacrolimus combination is not contraindicated, other treatment strategies should be considered first, if available, and the dose of tacrolimus should be reduced when using the nirmatrelvir-ritonavir combination. In cases where combination therapy is necessary, serum tacrolimus levels should be closely monitored in lung transplant recipients. Documentation of more such reports is important to identify drug interactions between nirmatrelvir-ritonavir and other agents, with the aim of preventing severe adverse effects.

Nirmatrelvir/ritonavir is a treatment for COVID-19 consisting of nirmatrelvir, which has anti-SARS-CoV-2 activity, and ritonavir, a booster to maintain blood levels. Ritonavir is known to be a potent inhibitor of cytochrome P450 3A (CYP3A), and interactions with CYP3A-metabolized drugs, such as the immunosuppressant tacrolimus, can be problematic. Ritonavir\'s inhibition of CYP3A is irreversible due to covalent binding, and its inhibitory effects are expected to persist until replaced by new CYP3A. Here, we report a case where the combination of nirmatrelvir/ritonavir and tacrolimus resulted in toxic tacrolimus blood levels. A patient on tacrolimus for systemic lupus erythematosus (SLE) developed COVID-19 and was prescribed nirmatrelvir/ritonavir. After starting the combination of nirmatrelvir/ritonavir and tacrolimus, the patient\'s tacrolimus blood levels became abnormally high, leading to the discontinuation of these drugs due to symptoms of tacrolimus toxicity. Even after ritonavir blood levels had fallen below the detection limit, the decline in tacrolimus blood levels was delayed. The CYP3A inhibition of ritonavir persists even when its blood concentration decreases, emphasizing the need for careful consideration of concomitant medications before starting nirmatrelvir/ritonavir therapy. Adjustments or discontinuation may be necessary.

OBJECTIVE: Nirmatrelvir/ritonavir is one of few options for outpatient treatment of COVID-19, but its use has been limited in transplant recipients due to significant drug interactions with immunosuppressants. Tacrolimus toxicity is possible when the drug is coadministered with nirmatrelvir/ritonavir and may require urgent reduction of tacrolimus levels. This case series describes the use of phenytoin for enzyme induction in 5 adult solid organ transplant recipients with supratherapeutic tacrolimus levels resulting from coadministration with nirmatrelvir/ritonavir.
CONCLUSIONS: Solid organ transplant recipients are at high risk for complications related to COVID-19. Outpatient treatment options are limited, and therapeutic drug monitoring is complex in patients requiring quarantine. The 5 solid organ transplant recipients described herein were initiated on nirmatrelvir/ritonavir in the outpatient setting and subsequently presented with supratherapeutic tacrolimus concentrations greater than 59 ng/mL and developed signs and symptoms of tacrolimus toxicity. In all patients, nirmatrelvir/ritonavir and tacrolimus were discontinued, and oral phenytoin (200-400 mg/day) was given for 2 to 4 days. Tacrolimus was resumed once tacrolimus levels decreased to appropriate levels.
CONCLUSIONS: These observations demonstrate that metabolism induction using phenytoin may be a useful strategy in the setting of supratherapeutic tacrolimus levels resulting from concomitant administration with nirmatrelvir/ritonavir.

With the improving life expectancy of patients with human immunodeficiency virus (HIV), there is an increasing health concern of potential toxicity and drug interactions of long-term antiretroviral therapies. We describe a female patient with HIV, who was admitted to the emergency department following an unexplained loss of consciousness. This patient had been on antiretroviral therapy comprising tenofovir disoproxil fumarate, lamivudine, and lopinavir/ritonavir for 12 years. Coincidentally, she had been prescribed terfenadine for urticaria recently. After 3 days on this medication, she suddenly lost her consciousness, with a distinctive electrocardiogram alteration characterized by QT prolongation and torsade de pointes. This symptom recurred several times over a span of 2 days. We postulate that the primary instigator was an elevated concentration of terfenadine, which can be traced back to her antiretroviral therapy regimen comprising lopinavir/ritonavir. This drug is known to impede the metabolism of cytochrome P450 3A4 substrates and consequently elevate terfenadine concentrations.

We report a rare case of rhabdomyolysis in a 64-year-old man who had been receiving long-term statin therapy for hyperlipidemia. The patient initially presented with symptoms of acute appendicitis, which later progressed to acute renal failure and rhabdomyolysis. No commonly identified risk factors for rhabdomyolysis, including drug interactions and statin doses, were observed. The patient was urgently admitted to the intensive care unit where the relevant medications were discontinued in a timely manner and infusion resuscitation was performed. Renal function and serum creatine kinase levels gradually stabilized without the need for hemodialysis. After four days, the patient was transferred to a general ward and was fully discharged from the hospital 13 days after admission. This case highlights the importance of considering rhabdomyolysis as a possible complication among patients receiving statin therapy, even in the absence of traditional risk factors.

BACKGROUND: Up to 1/2 of outpatients prescribed clozapine may be partially/fully non-adherent, based on therapeutic drug monitoring (TDM). Three indices for measuring partial/full non-adherence are proposed a: 1) clozapine concentration/dose (C/D) ratio which drops to half or more of what is expected in the patient; 2) clozapine/norclozapine ratio that becomes inverted; and 3) clozapine concentration that becomes non-detectable.
METHODS: These 3 proposed indices are based on a literature review and 17 cases of possible non-adherence from 3 samples: 1) an inpatient study in a Chinese hospital, 2) an inpatient randomized clinical trial in a United States hospital, and 3) and a Uruguayan outpatient study.
RESULTS: The first index of non-adherence is a clozapine C/D ratio which is less than half the ratio corresponding to the patient\'s specific ancestry group and sex-smoking subgroup. Knowing the minimum therapeutic dose of the patient based on repeated TDM makes it much easier to establish non-adherence. The second index is inverted clozapine/norclozapine ratios in the absence of alternative explanations. The third index is undetectable concentrations. By using half-lives, the chronology of the 3 indices of non-adherence was modeled in two patients: 1) the clozapine C/D ratio dropped to ≥1/2 of what is expected from the patient (around day 2); 2) the clozapine/norclozapine ratio became inverted (around day 3); and 3) the clozapine concentration became undetectable by the laboratory (around days 9-11).
CONCLUSIONS: Prospective studies should further explore these proposed clozapine indices in average patients, poor metabolizers (3 presented) and ultrarapid metabolizers (2 presented).