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Drug Interactions between Prezcobix and QM-260

This report displays the potential drug interactions for the following 2 drugs:

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Interactions between your drugs

Moderate

quiNINE darunavir

Applies to: QM-260 (quinine) and Prezcobix (cobicistat / darunavir)

MONITOR: Coadministration with inhibitors of CYP450 3A4 may increase the plasma concentrations of quinine, which is primarily metabolized by the isoenzyme. In ten healthy volunteers, administration of a single 600 mg oral dose of quinine sulfate in combination with the potent CYP450 3A4 inhibitor troleandomycin (500 mg orally every 8 hours for 48 hours) significantly increased the mean quinine peak plasma concentration (Cmax), systemic exposure (AUC) and terminal elimination half-life by 26%, 90% and 63%, respectively, and decreased the mean oral clearance (Cl/F) by 45% compared to administration of quinine alone. Troleandomycin also reduced the average Cmax, AUC and apparent formation clearance of the main metabolite, 3-hydroxyquinine, by 75%, 58% and 81%, respectively. Likewise, in a study of nine healthy volunteers, administration of a single 500 mg oral dose of quinine hydrochloride in combination with another potent CYP450 3A4 inhibitor ketoconazole (100 mg twice daily for 3 days) resulted in a 45% increase in mean quinine AUC and a 31% decrease in mean oral clearance compared to administration of quinine alone. Clinically, high plasma levels of quinine may increase the risk of QT interval prolongation, which has been associated with ventricular arrhythmias including torsade de pointes and sudden death. Fatal torsade de pointes arrhythmia was reported in an elderly patient who received quinine in combination with erythromycin, a moderately potent CYP450 3A4 inhibitor, and dopamine. However, a causal relationship was not established in this case. The risk of other quinine toxicities such as cinchonism may also be increased.

MANAGEMENT: Caution is advised if quinine is used in combination with potent and moderate CYP450 3A4 inhibitors. Patients should be monitored closely for adverse reactions associated with quinine such as hematologic toxicities and cardiac arrhythmias including torsade de pointes and atrial fibrillation. Patients should be advised to contact their physician if they experience increased side effects such as headache, flushing, sweating, nausea, vomiting, diarrhea, abdominal pain, tinnitus, dizziness, vertigo, hearing impairment, blurred vision, vision impairment, and irregular heart rhythm.

References

  1. Zhao XJ, Ishizaki T "Metabolic interactions of selected antimalarial and non-antimalarial drugs with the major pathway (3-hydroxylation) of quinine in human liver microsomes." Br J Clin Pharmacol 44 (1997): 505-11
  2. Mirghani RA, Hellgren U, Westerberg PA, Ericsson O, Bertilsson L, Gustafsson LL "The roles of cytochrome P450 3A4 and 1A2 in the 3-hydroxylation of quinine in vivo." Clin Pharmacol Ther 66 (1999): 454-60
  3. Zhao XJ, Ishizaki T "A further interaction study of quinine with clinically important drugs by human liver microsomes: determinations of inhibition constant (K-i) and type of inhibition." Eur J Drug Metab Pharm 24 (1999): 272-8
  4. Wanwimolruk S, Paine MF, Pusek SN, Watkins PB "Is quinine a suitable probe to assess the hepatic drug-metabolizing enzyme CYP3A4?" Br J Clin Pharmacol 54 (2002): 643-51
  5. Mirghani RA, Ericsson O, Tybring G, Gustafsson LL, Bertilsson L "Quinine 3-hydroxylation as a biomarker reaction for the activity of CYP3A4 in man." Eur J Clin Pharmacol 59 (2003): 23-8
  6. Mirghani RA, Hellgren U, Bertilsson L, Gustafsson LL, Ericsson O "Metabolism and elimination of quinine in healthy volunteers." Eur J Clin Pharmacol (2003):
  7. Cerner Multum, Inc. "UK Summary of Product Characteristics." O 0
  8. "Product Information. Qualaquin (quinine)." AR Scientific Inc (2006):
  9. Cerner Multum, Inc. "Australian Product Information." O 0
  10. Zhang H, Coville PF, Walker RJ, Miners JO, Birkett DJ, Wanwimolruk S "Evidence for involvement of human CYP3A in the 3-hydroxylation of quinine." Br J Clin Pharmacol 43 (1997): 245-52
  11. Mirghani RA, Yasar U, Zheng T, et al. "Enzyme kinetics for the formation of 3-hydroxyquinine and three new metabolites of quinine in vitro; 3-hydroxylation by CYP3A4 is indeed the major metabolic pathway." Drug Metab Dispos 30 (2002): 1368-71
View all 11 references

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Moderate

quiNINE cobicistat

Applies to: QM-260 (quinine) and Prezcobix (cobicistat / darunavir)

MONITOR: Coadministration with inhibitors of CYP450 3A4 may increase the plasma concentrations of quinine, which is primarily metabolized by the isoenzyme. In ten healthy volunteers, administration of a single 600 mg oral dose of quinine sulfate in combination with the potent CYP450 3A4 inhibitor troleandomycin (500 mg orally every 8 hours for 48 hours) significantly increased the mean quinine peak plasma concentration (Cmax), systemic exposure (AUC) and terminal elimination half-life by 26%, 90% and 63%, respectively, and decreased the mean oral clearance (Cl/F) by 45% compared to administration of quinine alone. Troleandomycin also reduced the average Cmax, AUC and apparent formation clearance of the main metabolite, 3-hydroxyquinine, by 75%, 58% and 81%, respectively. Likewise, in a study of nine healthy volunteers, administration of a single 500 mg oral dose of quinine hydrochloride in combination with another potent CYP450 3A4 inhibitor ketoconazole (100 mg twice daily for 3 days) resulted in a 45% increase in mean quinine AUC and a 31% decrease in mean oral clearance compared to administration of quinine alone. Clinically, high plasma levels of quinine may increase the risk of QT interval prolongation, which has been associated with ventricular arrhythmias including torsade de pointes and sudden death. Fatal torsade de pointes arrhythmia was reported in an elderly patient who received quinine in combination with erythromycin, a moderately potent CYP450 3A4 inhibitor, and dopamine. However, a causal relationship was not established in this case. The risk of other quinine toxicities such as cinchonism may also be increased.

MANAGEMENT: Caution is advised if quinine is used in combination with potent and moderate CYP450 3A4 inhibitors. Patients should be monitored closely for adverse reactions associated with quinine such as hematologic toxicities and cardiac arrhythmias including torsade de pointes and atrial fibrillation. Patients should be advised to contact their physician if they experience increased side effects such as headache, flushing, sweating, nausea, vomiting, diarrhea, abdominal pain, tinnitus, dizziness, vertigo, hearing impairment, blurred vision, vision impairment, and irregular heart rhythm.

References

  1. Zhao XJ, Ishizaki T "Metabolic interactions of selected antimalarial and non-antimalarial drugs with the major pathway (3-hydroxylation) of quinine in human liver microsomes." Br J Clin Pharmacol 44 (1997): 505-11
  2. Mirghani RA, Hellgren U, Westerberg PA, Ericsson O, Bertilsson L, Gustafsson LL "The roles of cytochrome P450 3A4 and 1A2 in the 3-hydroxylation of quinine in vivo." Clin Pharmacol Ther 66 (1999): 454-60
  3. Zhao XJ, Ishizaki T "A further interaction study of quinine with clinically important drugs by human liver microsomes: determinations of inhibition constant (K-i) and type of inhibition." Eur J Drug Metab Pharm 24 (1999): 272-8
  4. Wanwimolruk S, Paine MF, Pusek SN, Watkins PB "Is quinine a suitable probe to assess the hepatic drug-metabolizing enzyme CYP3A4?" Br J Clin Pharmacol 54 (2002): 643-51
  5. Mirghani RA, Ericsson O, Tybring G, Gustafsson LL, Bertilsson L "Quinine 3-hydroxylation as a biomarker reaction for the activity of CYP3A4 in man." Eur J Clin Pharmacol 59 (2003): 23-8
  6. Mirghani RA, Hellgren U, Bertilsson L, Gustafsson LL, Ericsson O "Metabolism and elimination of quinine in healthy volunteers." Eur J Clin Pharmacol (2003):
  7. Cerner Multum, Inc. "UK Summary of Product Characteristics." O 0
  8. "Product Information. Qualaquin (quinine)." AR Scientific Inc (2006):
  9. Cerner Multum, Inc. "Australian Product Information." O 0
  10. Zhang H, Coville PF, Walker RJ, Miners JO, Birkett DJ, Wanwimolruk S "Evidence for involvement of human CYP3A in the 3-hydroxylation of quinine." Br J Clin Pharmacol 43 (1997): 245-52
  11. Mirghani RA, Yasar U, Zheng T, et al. "Enzyme kinetics for the formation of 3-hydroxyquinine and three new metabolites of quinine in vitro; 3-hydroxylation by CYP3A4 is indeed the major metabolic pathway." Drug Metab Dispos 30 (2002): 1368-71
View all 11 references

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Drug and food interactions

Moderate

darunavir food

Applies to: Prezcobix (cobicistat / darunavir)

ADJUST DOSING INTERVAL: Food enhances the absorption and oral bioavailability of darunavir administered in combination with low-dose ritonavir. The mechanism is unknown. When administered with food, the peak plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) of darunavir were approximately 30% higher than when administered in the fasting state. Darunavir exposure was similar for the range of meals studied. The total caloric content of the various meals evaluated ranged from 240 Kcal (12 grams fat) to 928 Kcal (56 grams fat).

MANAGEMENT: To ensure maximal oral absorption, darunavir coadministered with ritonavir should be taken with food. The type of food is not important.

References

  1. "Product Information. Prezista (darunavir)." Ortho Biotech Inc (2006):

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Minor

quiNINE food

Applies to: QM-260 (quinine)

Coadministration with grapefruit juice does not appear to affect the pharmacokinetics of quinine in a clinically relevant manner. Although grapefruit juice is an inhibitor of CYP450 3A4 and quinine is metabolized by this pathway to its major metabolite, 3-hydroxyquinine, a study of ten healthy volunteers found no significant differences in quinine peak plasma concentration (Cmax), time to reach Cmax (Tmax), terminal elimination half-life, systemic exposure (AUC), or apparent oral clearance (Cl/F) when a single 600 mg oral dose of quinine sulfate was administered in combination with 200 mL of orange juice (control), half-strength grapefruit juice, and full-strength grapefruit juice twice daily for 6 days each, separated by a 2-week washout period. Relative to the control period, the apparent renal clearance of quinine was markedly increased by 81% during treatment with half-strength grapefruit juice. However, since renal clearance accounts for approximately 6% of the total clearance of quinine, this change would likely have minimal clinical impact. The lack of a significant interaction is probably due to the fact that grapefruit juice primarily inhibits intestinal rather than hepatic CYP450 3A4, and quinine is not known to undergo significant presystemic metabolism as evidenced by its relatively high oral bioavailability (76% to 88%). Nevertheless, excessive consumption of grapefruit juice and tonic water (which contains quinine) was suspected as the cause of torsade de pointes arrhythmia in a patient with a history of asymptomatic long QT syndrome. Treatment with magnesium sulfate and metoprolol had no effect, but the arrhythmia resolved spontaneously 48 hours after discontinuation of the drinks. Based on current data, moderate grapefruit juice consumption is probably safe for the majority of patients taking quinine.

References

  1. Ho PC, Chalcroft SC, Coville PF, Wanwimolruk S "Grapefruit juice has no effect on quinine pharmacokinetics." Eur J Clin Pharmacol 55 (1999): 393-8
  2. Hermans K, Stockman D, Van den Branden F "Grapefruit and tonic: a deadly combination in a patient with the long QT syndrome." Am J Med 114 (2003): 511-2
  3. "Product Information. Qualaquin (quinine)." AR Scientific Inc (2006):
  4. Zhang H, Coville PF, Walker RJ, Miners JO, Birkett DJ, Wanwimolruk S "Evidence for involvement of human CYP3A in the 3-hydroxylation of quinine." Br J Clin Pharmacol 43 (1997): 245-52
  5. Mirghani RA, Yasar U, Zheng T, et al. "Enzyme kinetics for the formation of 3-hydroxyquinine and three new metabolites of quinine in vitro; 3-hydroxylation by CYP3A4 is indeed the major metabolic pathway." Drug Metab Dispos 30 (2002): 1368-71
View all 5 references

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Therapeutic duplication warnings

No warnings were found for your selected drugs.

Therapeutic duplication warnings are only returned when drugs within the same group exceed the recommended therapeutic duplication maximum.

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Drug Interaction Classification

These classifications are only a guideline. The relevance of a particular drug interaction to a specific individual is difficult to determine. Always consult your healthcare provider before starting or stopping any medication.
Major Highly clinically significant. Avoid combinations; the risk of the interaction outweighs the benefit.
Moderate Moderately clinically significant. Usually avoid combinations; use it only under special circumstances.
Minor Minimally clinically significant. Minimize risk; assess risk and consider an alternative drug, take steps to circumvent the interaction risk and/or institute a monitoring plan.
Unknown No interaction information available.

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