Study On Pharmacodynamics And Pharmacokinetics Of Three Antiretroviral Drugs In Chinese Patients With HIV Infection

BackgroundHighly active antiretroviral therapy (HAART) has been considered as the most effective way of treatment of HIV infection and/or AIDS diseases. Nevirapine is one of non-nucleoside reverse transcriptase inhibitors and was recommended as the first-line antiretroviral regimen by the guidelines of international AIDS society and USA panel. It is important and necessary to observe the relationship between nevirapine concentration and viralogical response and to evaluate the influence of patient characteristics on nevirapine concentrations and drug-related liver toxicity and skin rash. Due to the higher incidence of drug-related liver toxicity and skin rash in Chinese HIV-infected patients with the conventional dosage regimen, it is of interest to investigate the potential of nevirapine200mg once daily regimen. Lopinavir is one protease inhibitor and tenofovir is one of nucleotide reverse transcriptase inhibitors. As the major antiretrovials in salvage regimen, tenofovir and lopinavir have been proven valid in Chinese HIV-infected adults with first-line treatment failure. Thus it is important to investigate their pharmacokinetic features in Chinese HIV-infected patients for their effective and safe use.ObjectivesTo investigate the potential of nevirapine200mg once daily regimen in clinical practice and evaluate the relationship between nevirapine concentration and viralogical response and drug-related adverse events; to develop two high performance liquid chromatography methods coupled with UV detection for quantitative determination of lopinavir and ritonavir and tenofovir in human plasma and to investigate the pharmacokinetic features of lopinavir and tenofovir in the Chinese patients with HIV infection.MethodsThis was a prospective, multicentre cohort study with828HIV-infected patients receiving nevirapine as a part of their initial antiretroviral therapy between Jan2005and Dec2011. The trial was approved by institutional review boards and carried out in accordance with the Declaration of Helsinki and the principles of Good Clinical Practice. Written informed consent was obtained from each patient and the study protocol was approved by independent ethics committee of participating hospitals. During the treatment period, patients were monitored at baseline, week2,4,12,24,36, and48for clinical features (particularly severe adverse events), plasma nevirapine concentrations and laboratory values including blood routine examination, hepatic and renal function, hepatitis B (HBV) or hepatitis C (HCV) serological state, CD4cell counts and plasma viral load. Nevirapine plasma concentrations during the lead-in (200mg once daily) and steady-state (200mg twice daily) periods were compared.A total of16patients receiving tenofovir as a part of antiretroviral regimen were enrolled into the pharmacokinetic study. Written informed consent was obtained from each patient and the study protocol was approved by the ethics committee of Peking Union Medical College Hospital. Blood samples were collected before and0.5,1,1.5,2,2.5,3,4,6,8,10,12,16and24h after administration. Plasma samples were analyzed for lopinavir and tenofovir concentrations by using the developed HPLC assays in present study. WINONLIN software was used to compute the pharmacokinetic parameters.ResultsThe median nevirapine trough and peak concentration during the lead-in period were4.26μg/mL (IQR3.05-5.61) and5.07μg/mL (IQR3.92-6.44) respectively, which both exceeded the recommended thresholds of nevirapine plasma concentrations, e.g.3.0μg/mL and3.9μg/mL, even though significantly lower than the steady-state levels (6.15and6.51μg/mL, P=0.000). Baseline hepatic function had a moderate effect on median nevirapine trough concentrations at week2(4.25μg/mL vs.4.86μg/mL, for ALT<1.5×ULN and≥1.5×ULN, respectively, P=0.045). No significant difference was observed in median nevirapine trough concentration between lead-in and steady-state periods in patients with baseline ALT and AST level≥1.5×ULN, which was different from the patients with ALT/AST level<1.5ULN. The median trough concentrations were significantly higher in HIV/HCV co-infected patients than those without HCV at week48(8.16μg/mL vs.6.15μg/mL, P=0.004).The median nevirapine trough concentrations were3.23,6.60and6.73μg/mL in patients with viralogical failure, partial viralogical suppression and complete viralogical suppression respectively, however, the differences of nevirapine peak concentrations were not observed among the three groups. Compared to the patients with nevirapine trough concentration greater than3.0or3.9μg/mL, the patients with nevirapine trough concentration lower than3.0or3.9μg/mL had a higher risk of occurrence of viralogical failure. Compared with3.0ug/mL,3.9μg/mL was a better threshold of nevirapine trough concentration in Chinese population to predict viralogical failure with sensitivity of87.9%and specificity of90.0%.The univariate stratification analysis showed that HIV/HCV coinfection particularly in males, ALT and AST>1.25ULN, CD4>250/mm3were associated with liver toxicity, female, Wt<55Kg and CD4>250/mm were associated with severe liver toxicity. The multivariate logistic regression indicated that increased levels of ALT and AST and CD4cell counts were significantly associated with liver toxicity, increased CD4cell counts and low body weight were significantly associated with severe liver toxicity. The risk of liver toxicity was increased3.23times when NVP-Ctrough>H Hg/mL, particularly, the risk was increased3.77times when NVP-CtrOugh>10ug/mL in males. The risk of liver toxicity was increased2.36times when the last-time NVP-Ctrough was>5u.g/mL. ROC analysis showed that NVP-Ctrough threshold of>5ug/mL had high sensitivity and specificity to predict the occurrence of liver toxicity. The risk of liver toxicity was increased2.21times when the lead-in NVP-Ctrough was>6ug/mL. ROC analysis showed that NVP-Ctrough threshold of>6ug/mL had high sensitivity and specificity of predicting the occurrence of liver toxicity.The risk of skin rash was increased1.73times in females, however, HIV/HBV or HIV/HCV coinfection and elevated CD4cell counts were not associated with the drug related skin rash. The levels of MIG, IP-10and IFN-y in patients with rash were significantly higher than the healthy volunteers. Additionaly, the levels of MIG and IP-10at the time rash occurrence were significantly higher than the levels before and after the appearance of rash.The calibration curves were linear in the range of0.5-20ug/mL for LPV (r=0.9995) and0.05-5ug/mL for RTV (r=0.9999). The range of the calibration curve of tenofovir was20-2000ng/mL (r=0.9997). The precision, accuracy and stability of the assays were satisfactory. The pharmacokinetics of tenofovir in15Chinese HIV-infected patients complied with two-compartment model, and the steady pharmacokinetic parameters were as follows: Tm29.53±14.12h, Tmax1.20±0.47h, Cmax361.51±219.04ng/mL, AUC4077.50±1554.88ng*h/mL, CL/F80.89±21.49L/h respectively. Additionaly, the patients who were not coadministered with LPV showed longer T1/2compared to the patients with LPV coadministration. The non-compartment model PK parameters were as follows: T1/221.84±7.64h, Tmax1.33±0.45h, Cmax447.09±217.39ng/mL, Ctrough98.66±36.66ng/mL and AUC4074.7±1551.86ng*h/mL, CL/F45.77±13.05L/h respectively.ConclusionsThe200mg once daily regimen of nevirapine might be comparable to twice daily in plasma pharmacokinetics in Chinese patients with HIV infection. Hepatic function prior to nevirapine treatment and HIV/HCV coinfection were significantly associated with nevirapine concentrations.The incidence of viralogical failure was increased with the low nevirapine trough concentration;3.9μg/mL was a better threshold of nevirapine trough concentration in Chinese population to predict viralogical failure with sensitivity of87.9%and specificity of90.0%higher than the3.0μg/mLPatients with high NVP-Ctrough were at greater risk of liver toxicity, especially in males. The last-time NVP-Ctrough of≥5μg/mL or lead-in NVP-Ctrough of≥6μg/mL was a good target to predict the incidence of hepatotoxicity.The female patients were vulnerable to nevirapine related skin rash; the inflammatory cytokines of MIG and IP-10may play a main role in the immune pathogenesis of nevirapine related skin rash through the abnormality of immune response.Two simple, validated, sensitive and reproducible methods for quantifying the concentration of tenofovir, lopinavir and ritonavir in human plasma by high performance liquid chromatography coupled with UV detection have been reported. The pharmacokinetics of tenofovir in Chinese patients demonstrated longer half-life, increased Cmax, Ctrough and AUC compared with those in Caucasians. Coadministration with LPV would potentially affect the pharmacokinetics of TNF. The pharmacokinetic profiles of lopinavir in Chinese HIV-infected patients demonstrated delayed Tmax and significant individual differences.