Depression is the most common mental health disorder among HIV-infected patients. When treating HIV-infected patients with a selective serotonin reuptake inhibitor (SSRI), potential drug–drug interactions with antiretroviral agents have to be taken into account. We investigated the two-way pharmacokinetic drug–drug interaction and tolerability of concomitant administration of the SSRI citalopram and the HIV-1 integrase inhibitor raltegravir in healthy volunteers.
Methods
An open-label, crossover, two-period trial was conducted in 24 healthy volunteers. Subjects received the following treatments: citalopram 20 mg once daily for 2 weeks followed by the combination with raltegravir 400 mg twice daily for 5 days and after a washout period raltegravir 400 mg twice daily for 5 days. Intensive steady-state pharmacokinetic blood sampling was performed. Geometric mean ratios (GMRs) of the combination versus the reference treatment and 90% CIs were calculated for the area under the plasma concentration–time curve (AUC). CYP2C19 genotyping was performed because it influences N-demethylation of citalopram to desmethylcitalopram.
Results
A total of 22 healthy volunteers completed the trial. GMRs (90% CI) were 1.00 (0.98, 1.03) for citalopram AUC0–24h, 0.99 (0.88, 1.12) for desmethylcitalopram AUC0–24h and 0.77 (0.50, 1.19) for raltegravir AUC0–12h. Raltegravir plasma concentration 12 h after intake (C12h) did not change with concomitant use of citalopram. Within each CYP2C19 phenotype subgroup the citalopram metabolite-to-parent ratio, which is a measure for metabolic enzyme activity, was not influenced by concomitant raltegravir use.
Conclusions
Raltegravir does not influence the pharmacokinetics of citalopram and desmethylcitalopram. Citalopram did not change the pharmacokinetics of raltegravir in a clinically meaningful way. The combination was well tolerated and can be administered without dose adjustments. ClinicalTrials.gov NCT01978782.
References
1.
MorrisonM.F., PetittoJ.M., Ten HaveT.Depressive and anxiety disorders in women with HIV infection.Am J Psychiatry2002; 159: 789–796.
2.
PenceB.W., O'DonnellJ.K., GaynesB.N.Falling through the cracks: the gaps between depression prevalence, diagnosis, treatment, and response in HIV care.AIDS2012; 26: 656–658.
3.
PenzakS.R., ReddyY.S., GrimsleyS.R.Depression in patients with HIV infection.Am J Health Syst Pharm2000; 57: 376–386.
4.
CieslaJ.A., RobertsJ.E.Meta-analysis of the relationship between HIV infection and risk for depressive disorders.Am J Psychiatry2001; 158: 725–730.
5.
GonzalezJ.S., BatchelderA.W., PsarosC., SafrenS.A.Depression and HIV/AIDS treatment nonadherence: a review and meta-analysis.J Acquir Immune Defic Syndr2011; 58: 181–187.
6.
LimaV.D., GellerJ., BangsbergD.R.The effect of adherence on the association between depressive symptoms and mortality among HIV-infected individuals first initiating HAART.AIDS2007; 21: 1175–1183.
7.
UthmanO.A., MagidsonJ.F., SafrenS.A., NachegaJ.B.Depression and adherence to antiretroviral therapy in low-, middle- and high-income countries: a systematic review and meta-analysis.Curr HIV/AIDS Rep2014; 11: 291–307.
8.
BengtsonA.M., PenceB.W., O'DonnellJ.Improvements in depression and changes in quality of life among HIV-infected adults.AIDS Care2015; 27: 47–53.
9.
SherbourneC.D., HaysR.D., FleishmanJ.A.Impact of psychiatric conditions on health-related quality of life in persons with HIV infection.Am J Psychiatry2000; 157: 248–254.
10.
HimelhochS., MedoffD.R.Efficacy of antidepressant medication among HIV-positive individuals with depression: a systematic review and meta-analysis.AIDS Patient Care STDS2005; 19: 813–822.
11.
HillL., LeeK.C.Pharmacotherapy considerations in patients with HIV and psychiatric disorders: focus on antidepressants and antipsychotics.Ann Pharmacother2013; 47: 75–89.
12.
HorbergM.A., SilverbergM.J., HurleyL.B.Effects of depression and selective serotonin reuptake inhibitor use on adherence to highly active antiretroviral therapy and on clinical outcomes in HIV-infected patients.J Acquir Immune Defic Syndr2008; 47: 384–390.
13.
BrøsenK., NaranjoC.A.Review of pharmacokinetic and pharmacodynamic interaction studies with citalopram.Eur Neuropsychopharmacol2001; 11: 275–283.
von MoltkeL.L., GreenblattD.J., GrassiJ.M.Citalopram and desmethylcitalopram in vitro: human cytochromes mediating transformation, and cytochrome inhibitory effects.Biol Psychiatry1999; 46: 839–849.
16.
KobayashiK., ChibaK., YagiT.Identification of cytochrome P450 isoforms involved in citalopram N-demethylation by human liver microsomes.J Pharmacol Exp Ther1997; 280: 927–933.
17.
RochatB., AmeyM., GilletM., MeyerU.A., BaumannP.Identification of three cytochrome P450 isozymes involved in N-demethylation of citalopram enantiomers in human liver microsomes.Pharmacogenetics1997; 7: 1–10.
18.
HiemkeC., HartterS.Pharmacokinetics of selective serotonin reuptake inhibitors.Pharmacol Ther2000; 85: 11–28.
19.
Bezchlibnyk-ButlerK., AleksicI., KennedyS.H.Citalopram–a review of pharmacological and clinical effects.J Psychiatry Neurosci2000; 25: 241–254.
20.
ChangM., TybringG., DahlM.L., LindhJ.D.Impact of cytochrome P450 2C19 polymorphisms on citalopram/ escitalopram exposure: a systematic review and meta-analysis.Clin Pharmacokinet2014; 53: 801–811.
21.
YuB.N., ChenG.L., HeN.Pharmacokinetics of citalopram in relation to genetic polymorphism of CYP2C19.Drug Metab Dispos2003; 31: 1255–1259.
22.
WeissJ., DormannS.M., Martin-FacklamM., KerpenC.J., Ketabi-KiyanvashN., HaefeliW.E.Inhibition of P-glycoprotein by newer antidepressants.J Pharmacol Exp Ther2003; 305: 197–204.
23.
WeberC.C., KressmannS., OttM., FrickerG., MullerW.E.Inhibition of P-glycoprotein function by several antidepressants may not contribute to clinical efficacy.Pharmacopsychiatry2005; 38: 293–300.
HarrisM., LarsenG., MontanerJ.S.Exacerbation of depression associated with starting raltegravir: a report of four cases.AIDS2008; 22: 1890–1892.
27.
WenningL.A., FriedmanE.J., KostJ.T.Lack of a significant drug interaction between raltegravir and tenofovir.Antimicrob Agents Chemother2008; 52: 3253–3258.
28.
AndrewsE., GlueP., FangJ., CrownoverP., TresslerR., DamleB.Assessment of the pharmacokinetics of co-administered maraviroc and raltegravir.Br J Clin Pharmacol2010; 69: 51–57.
van LuinM., Van Der EndeM.E., RichterC.Lower atovaquone/proguanil concentrations in patients taking efavirenz, lopinavir/ritonavir or atazanavir/ritonavir.AIDS2010; 24: 1223–1226.
31.
ElensL., BouamarR., HesselinkD.A.A new functional CYP3A4 intron 6 polymorphism significantly affects tacrolimus pharmacokinetics in kidney transplant recipients.Clin Chem2011; 57: 1574–1583.
32.
BlonkM., ColbersA., PoirtersA., SchouwenbergB., BurgerD.Effect of ginkgo biloba on the pharmacokinetics of raltegravir in healthy volunteers.Antimicrob Agents Chemother2012; 56: 5070–5075.
33.
BurgerD., TeulenM., EerlandJ., HarteveldA., AarnoutseR., TouwD.The International Interlaboratory Quality Control Program for Measurement of Antiretroviral Drugs in Plasma: a global proficiency testing program.Ther Drug Monit2011; 33: 239–243.
34.
DiFrancescoR., TooleyK., RosenkranzS.L.Clinical pharmacology quality assurance for HIV and related infectious diseases research.Clin Pharmacol Ther2013; 93: 479–482.
MossD.M., KwanW.S., LiptrottN.J.Raltegravir is a substrate for SLC22A6: a putative mechanism for the interaction between raltegravir and tenofovir.Antimicrob Agents Chemother2011; 55: 879–887.
39.
CattaneoD., GervasoniC., MeravigliaP.Inter- and intra-patient variability of raltegravir pharmacokinetics in HIV-1-infected subjects.J Antimicrob Chemother2012; 67: 460–464.
40.
SiccardiM., D'AvolioA., Rodriguez-NovoaS.Intrapatient and interpatient pharmacokinetic variability of raltegravir in the clinical setting.Ther Drug Monit2012; 34: 232–235.
41.
FortunaS., FabbianiM., DigiambenedettoS.Variability of raltegravir plasma levels in the clinical setting.Pharmacology2013; 92: 43–48.
42.
MossD.M., SiccardiM., MurphyM.Divalent metals and pH alter raltegravir disposition in vitro.Antimicrob Agents Chemother2012; 56: 3020–3026.
43.
RizkM.L., HangY., LuoW.L.Pharmacokinetics and pharmacodynamics of once-daily versus twice-daily raltegravir in treatment-naive HIV-infected patients.Antimicrob Agents Chemother2012; 56: 3101–3106.
44.
MarkowitzM., Morales-RamirezJ.O., NguyenB.Y.Antiretroviral activity, pharmacokinetics, and tolerability of MK-0518, a novel inhibitor of HIV-1 integrase, dosed as monotherapy for 10 days in treatment-naive HIV-1-infected individuals.J Acquir Immune Defic Syndr2006; 43: 509–515.
