Interaction of Ritonavir-Boosted Tipranavir with Loperamide Does Not Result in Loperamide-Associated Neurologic Side Effects in Healthy Volunteers

Mukwaya, Geoffrey; MacGregor, Thomas R.; Hoelscher, David; Heming, Thomas A.; Legg, Daniel; Kavanaugh, Kelli; Johnson, P. C.; Sabo, John P.; McCallister, Scott

doi:10.1128/aac.49.12.4903-4910.2005

Cited by 54 publications

(39 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In contrast to loperamide, the pharmacokinetics of the primary CYP3A4-mediated metabolite, N-desmethylloperamide, were unchanged in the presence of GFJ, which may reflect elimination rate-limited kinetics and/or more rapid distribution into peripheral tissues relative to loperamide (Sklerov et al, 2005). The pharmacokinetics of both loperamide and N-desmethylloperamide in the absence of GFJ were consistent with those reported at an equivalent (16 mg) (Mukwaya et al, 2005) or lower (2-4 mg) (Streel et al, 2005;Niemi et al, 2006) loperamide dose after dose normalization.…”

Section: Discussionsupporting

confidence: 77%

Assessment of a Candidate Marker Constituent Predictive of a Dietary Substance–Drug Interaction: Case Study with Grapefruit Juice and CYP3A4 Drug Substrates

Ainslie¹,

Wolf²,

Li³

et al. 2014

J Pharmacol Exp Ther

View full text Add to dashboard Cite

Dietary substances, including herbal products and citrus juices, can perpetrate interactions with conventional medications. Regulatory guidances for dietary substance-drug interaction assessment are lacking. This deficiency is due in part to challenges unique to dietary substances, a lack of requisite human-derived data, and limited jurisdiction. An in vitro-in vivo extrapolation (IVIVE) approach to help address some of these hurdles was evaluated using the exemplar dietary substance grapefruit juice (GFJ), the candidate marker constituent 69,79-dihydroxybergamottin (DHB), and the purported victim drug loperamide. First, the GFJ-loperamide interaction was assessed in 16 healthy volunteers. Loperamide (16 mg) was administered with 240 ml of water or GFJ; plasma was collected from 0 to 72 hours. Relative to water, GFJ increased the geometric mean loperamide area under the plasma concentration-time curve (AUC) significantly (1.7-fold). Second, the mechanism-based inhibition kinetics for DHB were recovered using human intestinal microsomes and the index CYP3A4 reaction, loperamide N-desmethylation (K I [concentration needed to achieve one-half k inact ], 5.0 6 0.9 mM; k inact [maximum inactivation rate constant], 0.38 6 0.02 minute 21). These parameters were incorporated into a mechanistic static model, which predicted a 1.6-fold increase in loperamide AUC. Third, the successful IVIVE prompted further application to 15 previously reported GFJ-drug interaction studies selected according to predefined criteria. Twelve of the interactions were predicted to within the 25% predefined criterion. Results suggest that DHB could be used to predict the CYP3A4-mediated effect of GFJ. This time-and cost-effective IVIVE approach could be applied to other dietary substance-drug interactions to help prioritize new and existing drugs for more advanced (dynamic) modeling and simulation and clinical assessment.

show abstract

Section: Discussionsupporting

confidence: 77%

Assessment of a Candidate Marker Constituent Predictive of a Dietary Substance–Drug Interaction: Case Study with Grapefruit Juice and CYP3A4 Drug Substrates

Ainslie¹,

Wolf²,

Li³

et al. 2014

J Pharmacol Exp Ther

View full text Add to dashboard Cite

show abstract

“…Alternatively, absorption can be reduced via induction of these transporters. Clinically significant Pgp interactions have been reported with the PIs tipranavir/ritonavir and the Pgp substrate loperamide, resulting in a 50% reduction in the area under the curve (AUC) of loperamide (Mukwaya et al, 2005). Dolutegravir (DTG) is a tricyclic carbamoyl pyridone integrase inhibitor that blocks the strand transfer step during the integration of the HIV-1 DNA into the genome of the host cell.…”

Section: Introductionmentioning

confidence: 99%

In Vitro Investigations into the Roles of Drug Transporters and Metabolizing Enzymes in the Disposition and Drug Interactions of Dolutegravir, a HIV Integrase Inhibitor

et al. 2012

View full text Add to dashboard Cite

Dolutegravir (DTG; S/GSK1349572) is a potent HIV-1 integrase inhibitor with a distinct resistance profile and a once-daily dose regimen that does not require pharmacokinetic boosting. This work investigated the in vitro drug transport and metabolism of DTG and assessed the potential for clinical drug-drug interactions. DTG is a substrate for the efflux transporters P-glycoprotein (Pgp) and human breast cancer resistance protein (BCRP). Its high intrinsic membrane permeability limits the impact these transporters have on DTG's intestinal absorption. UDP-glucuronosyltransferase (UGT) 1A1 is the main enzyme responsible for the metabolism of DTG in vivo, with cytochrome P450 (P450) 3A4 being a notable pathway and UGT1A3 and UGT1A9 being only minor pathways. DTG demonstrated little or no inhibition (IC 50 values > 30 mM) in vitro of the transporters Pgp, BCRP, multidrug resistance protein 2, organic anion transporting polypeptide 1B1/3, organic cation transporter (OCT) 1, or the drug metabolizing enzymes CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4, UGT1A1, or 2B7. Further, DTG did not induce CYP1A2, 2B6, or 3A4 mRNA in vitro using human hepatocytes. DTG does inhibit the renal OCT2 (IC 50 = 1.9 mM) transporter, which provides a mechanistic basis for the mild increases in serum creatinine observed in clinical studies. These in vitro studies demonstrate a low propensity for DTG to be a perpetrator of clinical drug interactions and provide a basis for predicting when other drugs could result in a drug interaction with DTG.

show abstract

Section: Discussionmentioning

confidence: 99%

“…TPV (11) and, to a lesser extent, RTV (7) are substrates for P glycoprotein efflux transport. In a drug interaction study with the P glycoprotein substrate loperamide, TPV exhibited P glycoprotein self-induction capability (11). In long-term clinical trials with TPV and RTV, TPV has been shown to significantly reduce systemic RTV exposure (14), presumably due to P glycoprotein efflux transport.…”

Section: Discussionmentioning

confidence: 99%

“…Since RTV strongly inhibits cytochrome P450 3A4 (CYP3A4) (5), the boosted levels of TPV in plasma with the coadministration of TPV and RTV (TPV/r) indicate that the metabolism of TPV occurs via the cytochrome P450 (CYP450) pathway (8,9). Phase II studies have also demonstrated that TPV is an inducer of CYP450 metabolism or intestinal P glycoprotein efflux, thereby lowering systemic RTV concentrations when administered with RTV (8,11,14). Clinical studies with healthy volunteers and HIV-infected patients have evaluated potential drug interactions of TPV/r and established that no TPV dose adjustments are required when TPV/r is administered in conjunction with other commonly employed antiretroviral agents (13; F. D. Goebel, J. P. Sabo The purpose of the present study was to characterize the pharmacokinetic and metabolite profiles of TPV when administered with RTV.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Steady-State Disposition of the Nonpeptidic Protease Inhibitor Tipranavir when Coadministered with Ritonavir

Chen¹,

Sabo²,

Philip³

et al. 2007

Antimicrob Agents Chemother

Self Cite

View full text Add to dashboard Cite

The pharmacokinetic and metabolite profiles of the antiretroviral agent tipranavir (TPV), administered with ritonavir (RTV), in nine healthy male volunteers were characterized. Subjects received 500-mg TPV capsules with 200-mg RTV capsules twice daily for 6 days. They then received a single oral dose of 551 mg of TPV containing 90 Ci of [ 14 C]TPV with 200 mg of RTV on day 7, followed by twice-daily doses of unlabeled 500-mg TPV with 200 mg of RTV for up to 20 days. Blood, urine, and feces were collected for mass balance and metabolite profiling. Metabolite profiling and identification was performed using a flow scintillation analyzer in conjunction with liquid chromatography-tandem mass spectrometry. The median recovery of radioactivity was 87.1%, with 82.3% of the total recovered radioactivity excreted in the feces and less than 5% recovered from urine. Most radioactivity was excreted within 24 to 96 h after the dose of [ 14 C]TPV. Radioactivity in blood was associated primarily with plasma rather than red blood cells. Unchanged TPV accounted for 98.4 to 99.7% of plasma radioactivity. Similarly, the most common form of radioactivity excreted in feces was unchanged TPV, accounting for a mean of 79.9% of fecal radioactivity. The most abundant metabolite in feces was a hydroxyl metabolite, H-1, which accounted for 4.9% of fecal radioactivity. TPV glucuronide metabolite H-3 was the most abundant of the drug-related components in urine, corresponding to 11% of urine radioactivity. In conclusion, after the coadministration of TPV and RTV, unchanged TPV represented the primary form of circulating and excreted TPV and the primary extraction route was via the feces.

show abstract

Interaction of Ritonavir-Boosted Tipranavir with Loperamide Does Not Result in Loperamide-Associated Neurologic Side Effects in Healthy Volunteers

Cited by 54 publications

References 26 publications

Assessment of a Candidate Marker Constituent Predictive of a Dietary Substance–Drug Interaction: Case Study with Grapefruit Juice and CYP3A4 Drug Substrates

Assessment of a Candidate Marker Constituent Predictive of a Dietary Substance–Drug Interaction: Case Study with Grapefruit Juice and CYP3A4 Drug Substrates

In Vitro Investigations into the Roles of Drug Transporters and Metabolizing Enzymes in the Disposition and Drug Interactions of Dolutegravir, a HIV Integrase Inhibitor

Steady-State Disposition of the Nonpeptidic Protease Inhibitor Tipranavir when Coadministered with Ritonavir

Contact Info

Product

Resources

About